Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation

Article abstract of DOI:10.1021/acs.joc.9b01362

8-Aminoquinoline (AQ) is a widely used bidentate auxiliary in metal-catalyzed directed C-H functionalization reactions. Herein, we report an efficient and chemoselective method to convert various N-quinolyl carboxamides to primary amides with the treatment of a stoichiometric amount of 2-iodoxybenzoic acid oxidant or the combination of a catalytic amount of 2-iodobenzoic acid and Oxone co-oxidant in mixed solvents of H₂O and HFIP. Its unique compatibility with the Phth-protected α-amino acid (αAA) substrates enhances the overall synthetic utility of the AQ-directed palladium-catalyzed C-H functionalization strategy for synthesis of complex αAAs.

Full text of DOI:10.1021/acs.joc.9b01362

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Article
Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation
Zhiguo Zhang, Xiang Li, Mengmeng Song, Yameng Wan, Dan Zheng, Guisheng Zhang, and Gong Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01362 • Publication Date (Web): 06 Jun 2019
Downloaded from http://pubs.acs.org on June 10, 2019
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Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation
Zhiguo Zhang,*a Xiang Li,a Mengmeng Song,a Yameng Wan,a Dan Zheng,a Guisheng Zhang,*a and Gong
Chen*b
7
8
a Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic
Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China.
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b State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China.
TBN
O
O
IBX
O
AcOH
HFIP/H2O, 60 o
C
PhthN
R
PhthN
R
PhthN
R
NH2
N
OH
H
75 oC, 3 h
or 2-IBA, oxone
HFIP/H2O, 70 o
N
R'
R'
R'
C
C−N cleavage
Abstract: 8-Aminoquinoline (AQ) is a widely used bidentate auxiliary in metal-catalyzed directed C-H
functionalization reactions. Herein, we report an efficient and chemoselective method to convert various
N-quinoly carboxamides to primary amides with the treatment of stoichiometric amount of 2-
iodoxybenzoic acid (IBX) oxidant or the combination of catalytic amount of 2-iodobenzoic acid (2-IBA)
and Oxone co-oxidant in mixed solvents of H2O and HFIP. Its unique compatibility with the Phth-
protected a-amino acid (aAA) substrates enhances the overall synthetic utility of AQ-directed palladium-
catalyzed C-H functionalization strategy for synthesis of complex aAAs.
Key words: IBX; C(sp2)-N bond cleavage; metal-free; amino acids
Introduction
8-Aminoquinoline (AQ) has been widely used as a bidentate auxiliary in various metal-
catalyzed C-H functionalization reactions.1 A number of protocols, including hydrolysis or
alcoholysis of amide under acidic or basic conditions,2 Boc activation/LiOH cleavage,3
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Scheme 1. Removal of amide-linked AQ group.
ozonolysis/cleavage of imide;4 oxidative cleavage of 5-methoxy-8-aminoquinoline (MQ)5 and
Ni-catalyzed alcoholysis,6 have been reported for the removal of the AQ group, forming free
carboxylic acid or primary amide (Scheme 1). Despite these advances, important practical issues
such as chemoselectivity, functional group tolerance and racemization of chiral Ca remain to be
improved. Methods suitable for complex substrates such as peptides bearing different amide
groups are still greatly desired to achieve broader application of AQ-directed C-H
functionalization chemistry. Herein, we report an efficient and chemoselective method to convert
various
N-quinoly carboxamides to primary amides with the treatment of stoichiometric 2-
iodoxybenzoic acid (IBX) oxidant or the combination of catalytic 2-iodobenzoic acid (2-IBA) and
Oxone co-oxidant in mixed solvent of H2O and HFIP.7 Its unique compatibility with the Phth-
protected a-amino acid (aAA) substrates greatly enhances the overall synthetic utility of AQ-
directed palladium-catalyzed C-H functionalization strategy for synthesis of complex aAAs.
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Results and Discussion
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Recently, we demonstrated that reactions of
N
-aryl carboxamides featuring relatively electron-
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rich arenes with IBX in hexafluoro-2-propanol (HFIP) and water at room temperature undergo
C(aryl)-N cleavage to give primary amides in good yield and selectivity.8 Notably, mechanism of
the C(aryl)-N cleavage reaction was not well understood.9 Encouraged by that discovery, we
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wondered whether a similar operation can be used to remove the AQ auxiliary attached to N-Phth-
protected aAA substrates. Previous work from others and our lab have shown that palladium-
catalyzed AQ-directed side chain C-H functionalization offered a powerful strategy to construct
various complex aAA from simple aAA precursors.2b,10 However, facile removal of the AQ
group of the complex aAA products remains challenging especially for the sterically encumbered
b-disubstituted compounds.
As shown in Table 1, we were pleased to find that reaction of Ala substrate 1 with 2 equiv of IBX in
mixed solvents of HFIP and H2O (1:1) at 60 °C for 1.5 h gave primary amide product 2 in excellent
isolated yield (89%) and with excellent maintenance of chirality at Ca (> 99% ee) (entry 1). Quinoline-
7,8-dione 3 and 2-IBA 5 were identified as the by-products. Lower loading of IBX gave a lower
conversion of starting material (entries 2 and 3). Dess-Martin periodinane (DMP, I(V)) gave a slightly
lower yield than IBX (entry 4). Use of hydroxy benziodoxolone (BI-OH, I(III)) oxidant only gave a trace
amount of 2 (entry 5).11 Phenyliodonium diacetate (PIDA, I(III)) or iodosobenzene (PhIO, I(III)) gave 2
in low yield (entries 6 and 7). Interestingly, quinoline-5,8-dione 4 was isolated as the only quinolone
byproduct when the organoiodine (III) reagents were used. Use of ceric ammonium nitrate (CAN) gave a
complex mixture (entry 8).5 The mixed solvents of HFIP and H2O in 1:1 ratio is critical to obtain a high
yield of 2 (entries 1 vs 9 and 10). No reaction took place in the absence of H2O (entry 11). Other organic
solvents including 2,2,2-trifluoroethanol (TFE), DMSO, THF, and DMF gave much inferior results
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Table 1. Reaction Optimization of Phth-Ala-AQ 1.a
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Entry
Change from the standard conditions reagents
Time (h)
2 %
3 %
27 c
1 %
1
Standard conditions A
1.5
9
89 (75 b)
37
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< 5
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0
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2
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0
IBX (2 equiv) ® (1.0 equiv)
IBX (2 equiv) ® (1.5 equiv)
IBX ® DMP
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0
IBX ® BIOH
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0 d
0 d
0
IBX ® PIDA
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0
IBX ® PhIO
8 e
0
IBX ® CAN
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63
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< 5
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0
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< 5
0
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17
86
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93
44
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0
HFIP/H2O (1/1) ® HFIP/H2O (2/1)
HFIP/H2O (1/1) ® HFIP/H2O (1/2)
HFIP/H2O (1/1) ® HFIP
HFIP/H2O (1/1) ® TFE/H2O (1/1)
HFIP/H2O (1/1) ® DMSO/H2O (1/1)
HFIP/H2O (1/1) ® DMSO
HFIP/H2O (1/1) ® THF/H2O (1/1)
HFIP/H2O (1/1) ® DMF/H2O (1/1)
60 oC ® 40 oC
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1.5
11
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0
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< 5
0
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0
76
83
22
0
IBX ® 2-IBA (0.3 equiv)/Oxone (3 equiv) at 70 oC
0
(Standard conditions B)
a Unless otherwise indicated, reactions were conducted with 0.3 mmol of 1 in 2 mL of solvent at 60 °C,
isolated yield. b Isolated yield of 2 on a 3 mmol scale. c 59% yield of 3 based on 1H-NMR of crude reaction
d
e
mixture after workup. No 3 was formed; about 12% of 4 was isolated. Complex reaction mixture was
obtained.
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(entries 12-16). Reaction at 40 °C for 24 h gave a slightly lower yield of 2 (entry 17). A gram
scale reaction 1 (3 mmol scale) gave 2 in 75% isolated yield in 2 h (entry 1). As shown in entry
18, we were pleased to find that the combination of catalytic amount of 5 (0.3 equiv) and Oxone
co-oxidant (3 equiv) successfully gave product 2 in good yield (83%) in HFIP/H2O (1:1). The ee
value of 2 was slightly eroded (96% ee). IBX generated via in situ oxidation of 5 with Oxone was
likely responsible for the cleavage of AQ.12
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As shown in Scheme 2, the scope of AQ-coupled Phth-protected aAA substrates was next
evaluated under the optimized conditions A with IBX or conditions B with 2-IBA/Oxone. Many
of the corresponding AQ-coupled aAAs were prepared from simple aAA precursors via Pd-
10b,10g,10h
catalyzed AQ-directed C-H functionalization including alkylation (6-8),
arylation (13,
14, 17 and 18),10f,13 alkenylation (10),10d alkynylation (11),10e acetoxylation (15)14 and silylation
(16).10a-h,15 The cleavage reactions of the AQ-coupled secondary amides generally worked well to
give the primary amide products in excellent yield. Functional groups such as ester (8), BocNH
(9), olefin (10), alkyne (11) were well tolerated. In contrast, cleavage of AQ group from tertiary
amide 12, prepared via Pd-catalyzed AQ-directed intramolecular C-H amidation of a valine
precursor,5a failed to proceed with starting material largely recovered. As exemplified by 13 and
14, reaction of aAA bearing plain or alkyl-substituted aryl side chains proceeded cleanly to give
the amide products with little byproducts. b-Substituted Phe substrates (15, 16) also worked well.
In comparison, reaction of aAA bearing electron-rich alkoxy-substituted aryl groups gave the
desired products (e.g. 17 and 18) in moderate yield, along with a small amount of spirodienone
byproduct 19. 19 is likely formed via an IBX-mediated spirocyclization of primary amide
intermediates.16 Notably, reaction of Trp substrate 20 gave spiro-fused morpholine 21 in good
yield and excellent diastereoslectivity.17 The structure of 21 was confirmed by X-ray
crystallography. As exemplified by 8, 10, 11, 13, and 15, cleavage of AQ with 2-IBA/Oxone
under conditions B gave comparable results with conditions A.
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Scheme 2. Scope of AQ-Coupled aAAs.
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Reactions of other AQ-coupled substrates were next evaluated (Scheme 3). Reaction of Cbz
and Fmoc protected Ala substrates gave the corresponding amide products 22 and 23 in a slightly
lower yields (50% and 37%), along with small amounts of unidentified byproducts. Reaction of
Boc protected Ala gave a complex mixture (24). In contrast, Fmoc-protected dipeptide substrates
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Scheme 3. Scope of Other AQ-Coupled Substrates.
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with C-linked AQ group reacted cleanly to give the desired primary amide products (25-27),
suggesting the terminal carbamate and internal secondary and tertiary amide functional groups do
not interfere with the IBX-mediated removal of AQ. The reaction of a tripeptide substrate
proceeded with a lower conversion but gave the desired product (28) in high selectivity. Reaction
of AQ-coupled 3-phenylpropanamide gave product 29 in excellent yield.
N-quinolyl aryl
carboxamides also worked well (30 and 31). Notably, the normal -aryl carboxamide linkage of
N
32 was untouched possibly due to the deactivation by electron-withdraw carboxamide group on
the aniline moiety.
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As shown in equations 1 and 2, the resulting primary amide derivatives of aAA can be readily
converted to the free carboxylic acids with the treatment of tert-butyl nitrite (TBN) in AcOH at 75
oC.18 The Phth-protected Phe 33 was obtained in excellent yields and chiral integrity. The b-OAc
group of 34 was untouched.
Scheme 4 Mechanistic considerations.
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As outlined in Scheme 4A, the IBX-mediated removal of AQ group likely starts with the
substitution reaction of amide O atom of I with the iodo center of IBX to form iodoimidate II.19
The facile intramolecular proton transfer from NH to the pyridine N of AQ probably promotes the
amide tautomerization of I under slightly acidic conditions in FHIP, leading to the high reactivity
of the relatively electron deficient AQ group. Intramolecular nucleophilic attack of the oxo group
on the iodine center of II onto the ortho-position of AQ group triggers the de-aromatization of
aniline moiety and the cleavage of the O-I bond of II to form III.17,19 Deprotonation and cleavage
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of exocyclic O-I bond of III gives
o-iminoquinone species IV and 2-iodobenzoic acid 5.
Hydrolysis of IV gives the primary amides V and quinoline-7,8-dione 3.20 The diastereoselective
formation of morpholine 21 is consistent with an intramolecular [4+2] cycloaddition of o-
iminoquinone intermediate 37 with the side chain indole (Scheme 4B).17 In comparison, the
removal of AQ group with the treatment of PIDA could be explained by the intermolecular
nucleophilic attack of H2O to the C5 carbon of iodoimidate intermediate VI.21 Hydrolysis of
iminoquinone VII give the primary amide products and quinoline-5,8-dione 4 (Scheme 4C).22
p-
Conclusions
In summary, we have developed an efficient and selective method to remove the amide-linked
8-aminoquinoline auxiliary with IBX oxidant under mild conditions. We also demonstrated a
more economical protocol using a catalytic amount of 2-iodobenzoic acid and Oxone co-oxidant.
The reactions worked well with a variety of Phth-protected a-amino acid substrates bearing both
b-mono and di-substituted side chains. The reactions showed remarkable chemoselectivity of the
C-terminal
N
-quinolyl carboxamide without effecting the internal alkyl amide and common
-iminoquinone
carbamate protecting groups in peptides. Mechanistic studies indicated an
o
intermediate was generated via the intramolecular nucleophilic attack of the oxo group of
iodoimidate onto the ortho-position of AQ group. The resulting primary amides can be cleanly
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converted to free carboxylic acids with the treatment of TBN in AcOH. Overall, this method
complements the AQ-directed palladium-catalyzed C-H functionalization strategy for synthesis of
complex aAAs from simple precursors and would likely find broad application in other AQ-
directed reactions.
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Experimental section
General Remarks. All reagents were purchased from commercial sources and used without further
treatment, unless otherwise indicated. Other materials were prepared according to the literature.10a-h,13-15,20
Petroleum ether (PE) used here refers to the 60–90 °C boiling point fraction of petroleum. Ethyl acetate is
abbreviated as EA. 1H and 13C{1H} NMR spectra were recorded on a Bruker Avance/600 (1H: 600 MHz,
13C{1H}: 150 MHz at 25 °C) or Bruker Avance/400 (1H: 400 MHz, C{1H}: 100 MHz at 25 °C) with
13
tetramethylsilane as the internal standard. Data are represented as follows: chemical shift, integration,
multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, and m =
multiplet), and coupling constants in Hertz (Hz). All high-resolution mass spectra (HRMS) were
measured on a mass spectrometer by using electrospray ionization orthogonal acceleration time-of-flight
(ESI-OA-TOF), and the purity of all samples used for HRMS (>95%) was confirmed by 1H and 13C{1H}
NMR spectroscopic analysis. Melting points were measured on a melting point apparatus equipped with a
thermometer and were uncorrected. All reactions were monitored by thin-layer chromatography (TLC)
with GF254 silica gel-coated plates, and in general, the reaction was assumed to have completed 20 min
after the starting material 1 was completely consumed. Flash chromatography was carried out on SiO2
(silica gel 200–300 mesh).
Typical Experimental Procedure:
：
Removal of AQ under Conditions A on a 0.3 mol scale To a round-bottom flask (25 mL) were
added (S)-2-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl) propanamide 1 (104 mg, 0.3 mmol) and IBX
(168 mg, 0.6 mmol). The mixture in 2 mL of mixed-solvent (VHFIP/VH2O = 1:1) was stirred at 60 °C in oil
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bath under air atmosphere for 1.5 h (monitored by TLC). The reaction was quenched by the addition of
NaHCO3 (aq. 10 mL); the resulting mixture was extracted with dichloromethane (3 × 5 mL). The organic
solvent was concentrated in vacuo. The resulting residue was purified by silica gel flash column
chromatography using ethyl acetate (EA) and petroleum ether (PE) as eluent to give primary amide
product 2 as a white solid (58 mg, 89%).
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Removal of AQ under Conditions B on a 0.3 mol scale: To a round-bottom flask (25 mL) were added
(S)-2-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl) propanamide 1 (104 mg, 0.3 mmol), 2-IBA (22 mg,
0.09 mmol) and Oxone (553 mg, 0.9 mmol). The mixture in 2 mL of mixed-solvent (VHFIP/VH2O = 1:1)
was stirred at 70 °C for 5 h. The reaction was quenched by the addition of NaHCO3 (aq. 10 mL); the
resulting mixture was extracted with dichloromethane (3 × 5 mL). The organic solvent was concentrated
in vacuo; the resulting residue was purified by silica gel flash column chromatography using EA and PE
as eluent to give primary amide product 2 as a white solid (54 mg, 83%).
Conversion of primary amide to carboxylic acid: To a stirred solution of primary amide 13 (88 mg,
0.3 mmol) in acetic acid (2 mL) was slowly added tert-butyl nitrite (178 µL, 1.5 mmol). The reaction
mixture was stirred at 75 oC under air atmosphere for 3 h while the progress was monitored by TLC. The
reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel flash column
chromatography using EA and PE as eluent to give the free carboxylic acid product 33 as a white solid
(83 mg, 94%).18
：
Removal of AQ under Conditions A on a 3 mol scale To a round-bottom flask (50 mL) were added
(S)-2-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl) propanamide 1 (1.04 g, 3 mmol) and IBX (1.68 g, 6
mmol). The mixture in 10 mL of mixed-solvents (VHFIP/VH2O = 1:1) was stirred at 60 °C in oil bath under
air atmosphere for 2 h. The reaction was quenched by the addition of NaHCO3 (aq. 20 mL); the resulting
mixture was extracted with dichloromethane (3 × 10 mL). Then the organic solvent was concentrated in
vacuo. The residue was purified by flash column chromatography with EA and PE as eluent to give
primary amide 2 as a white solid (490 mg, 75%).
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(S)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2). The product was isolated by flash chromatography
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o
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(eluent: EA/PE = 1/2) as a white solid (58 mg, 89%): mp: 208-211 C; H NMR (400 MHz, CDCl3) δ
7.87 (dd, J = 5.2, 3.2 Hz, 2H), 7.75 (dd, J = 5.6, 3.2 Hz, 2H), 6.02 (s, 1H), 5.65 (s, 1H), 4.95 (q, J = 7.4
Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 171.4, 167.8, 134.4, 131.8, 123.6,
49.2, 15.4. HRMS (ESI), m/z calcd. for C11H10N2NaO3 ([M+Na]+) 241.0584, found: 241.0584.
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Quinoline-7,8-dione (3). The product was isolated by flash chromatography (eluent: EA) as a white
solid (13 mg, 27%): mp: 160-162 oC; 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J = 4.8, 1.6 Hz, 1H), 7.80
(dd, J = 8.0, 1.6 Hz, 1H), 7.59 (dd, J = 7.6, 4.4 Hz, 1H), 7.48 (d, J = 10.0 Hz, 1H), 6.58 (d, J = 10.0 Hz,
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1H). C{1H} NMR (100 MHz, CDCl3) δ 179.7, 178.3, 151.6, 147.4, 142.8, 137.0, 132.1, 129.3, 128.7.
HRMS (ESI), m/z calcd. for C9H6NO2 ([M+H]+) 160.0393, found: 160.0373.
Quinoline-5,8-dione (4). The product was isolated by flash chromatography (eluent: EA) as a white
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solid (6 mg, 12%): mp: 128-129 C; H NMR (400 MHz, CDCl3) δ 9.07 (dd, J = 4.8, 2.0 Hz, 1H), 8.43
(dd, J = 8.0, 1.6 Hz, 1H), 7.72 (dd, J = 8.0, 4.4 Hz, 1H), 7.17 (d, J = 10.8 Hz, 1H), 7.07 (d, J = 10.4 Hz,
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1H). C{1H} NMR (100 MHz, CDCl3) δ 184.5, 183.2, 154.8, 147.4, 139.1, 138.0, 134.6, 129.1, 127.9.
HRMS (ESI), m/z calcd. for C9H5NaNO2 ([M+Na]+) 182.0212, found: 182.0211.
(S)-2-(1,3-Dioxoisoindolin-2-yl)-3-methylbutanamide (6). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/2) as a white solid (56 mg, 76%): mp: 176-178oC; H NMR (600
MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.79-7.75 (m, 2H), 6.95 (s, 1H), 6.03 (s, 1H), 4.40 (d, J = 11.4 Hz,
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1H), 2.89-2.81 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). C{1H} NMR (100 MHz,
CDCl3) δ 171.3, 168.4, 134.5, 131.4, 123.7, 62.9, 27.6, 19.8, 19.5. HRMS (ESI), m/z calcd. for
C13H14N2NaO3 ([M+Na]+) 269.0897, found: 269.0890.
(S)-2-(1,3-Dioxoisoindolin-2-yl)pentanamide (7). The product was isolated by flash chromatography
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(eluent: EA/PE = 1/2) as a white solid (66 mg, 90%): mp: 160-162 C; 1H NMR (600 MHz, CDCl3) δ
7.88-7.83 (m, 2H), 7.74 (m, 2H), 6.27 (s, 1H), 5.92 (s, 1H), 4.80 (dd, J = 10.8, 4.8 Hz, 1H), 2.33-2.27 (m,
1H), 2.08-2.03 (m, 1H), 1.33-1.27 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ
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171.6, 168.4, 134.4, 131.6, 123.6, 54.3, 30.8, 19.6, 13.4. HRMS (ESI), m/z calcd. for C13H14N2NaO3
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([M+Na]+) 269.0897, found: 269.0898.
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Methyl (S)-5-amino-4-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (8). The product was isolated by
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flash chromatography (eluent: EA/PE = 2/1) as a white solid (74 mg, 85%); mp: 144-147 C; H NMR
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(600 MHz, CDCl3) δ 7.85-7.83 (m, 2H), 7.76-7.72 (m, 2H), 6.38 (s, 1H), 5.99 (s, 1H), 4.82 (dd, J = 9.6,
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6.0 Hz, 1H), 3.59 (s, 3H), 2.56-2.48 (m, 2H), 2.40-2.30 (m, 2H). C{1H} NMR (150 MHz, CDCl3) δ
172.9, 170.6, 168.0, 134.5, 131.6, 123.7, 53.2, 51.9, 30.9, 24.2. HRMS (ESI), m/z calcd. for
C14H14N2NaO5 ([M+Na]+) 313.0795, found: 313.0798.
tert-Butyl (S)-(6-amino-5-(1,3-dioxoisoindolin-2-yl)-6-oxohexyl)carbamate (9). The product was
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isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (90 mg, 80%): mp: 119-121 C;
1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 5.4, 3.0 Hz, 2H), 7.75 (dd, J = 5.4, 3.0 Hz, 2H), 6.34 (s, 1H),
5.69 (s, 1H), 4.79 (dd, J = 10.6, 5.4 Hz, 1H), 4.55 (s, 1H), 3.20-3.01 (m, 2H), 2.39-2.27 (m, 1H), 2.23-
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2.12 (m, 1H), 1.58-1.46 (m, 2H), 1.39 (s, 9H), 1.35-1.27 (m, 2H). C{1H} NMR (100 MHz, CDCl3) δ
171.1, 168.1, 156.1, 134.4, 131.6, 123.7, 54.4, 39.8, 29.3, 28.4, 23.5. HRMS (ESI), m/z calcd. for
C19H25N3NaO5 ([M+Na]+) 398.1686, found: 398.1682.
Methyl (S)-6-amino-5-(1,3-dioxoisoindolin-2-yl)-6-oxohex-2-enoate (10). The product was isolated
by flash chromatography (eluent: EA/PE = 1/1) as a white solid (77 mg, 86%): mp: 156-159 oC; 1H NMR
(400 MHz, CDCl3) δ 7.89-7.81 (m, 2H), 7.80-7.72 (m, 2H), 6.83-6.75 (m, 1H), 6.25 (s, 1H), 5.96 (s, 1H),
5.90-5.82 (m, 1H), 4.92 (dd, J = 10.4, 5.2 Hz, 1H), 3.62 (s, 3H), 3.24-3.03 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3) δ 170.1, 167.7, 166.2, 143.2, 134.6, 131.4, 124.6, 123.8, 52.6, 51.6, 31.5. HRMS (ESI), m/z
calcd. for C15H14N2NaO5 ([M+Na]+) 325.0795, found: 325.0786.
(S)-2-(1,3-Dioxoisoindolin-2-yl)-5-(triisopropylsilyl)pent-4-ynamide (11). The product was isolated
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by flash chromatography (eluent: EA/PE = 1/1) as a white solid (112 mg, 94%): mp: 193-194 C; H
NMR (600 MHz, CDCl3) δ 7.86 (dd, J = 5.4, 3.0 Hz, 2H), 7.74 (dd, J = 5.4, 3.0 Hz, 2H), 6.34 (s, 1H),
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5.76 (s, 1H), 5.00 (dd, J = 9.6, 6.6 Hz, 1H), 3.29-3.14 (m, 2H), 0.89-0.82 (m, 21H). C{1H} NMR (150
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MHz, CDCl3) δ 169.7, 167.7, 134.4, 131.7, 123.7, 103.0, 84.4, 52.5, 20.8, 18.4, 11.0. HRMS (ESI), m/z
calcd. for C22H30N2NaO3Si ([M+Na]+) 421.1918, found: 421.1916.
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2-((3S)-4-Methyl-2-oxo-1-(quinolin-8-yl)pyrrolidin-3-yl)isoindoline-1,3-dione (12). The product
was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (93% of starting material
was recovered): mp: 73-75 oC; 1H NMR (400 MHz, CDCl3) δ 8.93 (dd, J = 4.0, 1.6 Hz, 1H), 8.18 (dd, J =
8.4, 1.6 Hz, 1H), 7.90 (m, 3H), 7.79 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (dd, J = 5.4, 3.0 Hz, 3H), 7.59 (t, J =
7.8, 1H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), 4.27 (t, J = 9.6 Hz, 1H), 4.01 (dd, J =
9.6, 8.4 Hz, 1H), 3.25-3.13 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.9,
167.8, 150.0, 144.0, 136.2, 135.9, 134.1, 132.1, 129.4, 128.5, 127.5, 126.4, 123.5, 121.4, 57.8, 55.4, 33.6,
16.3. HRMS (ESI), m/z calcd. for C22H18N3O3 ([M+H]+) 372.1343, found: 372.1345.
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(S)-2-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropanamide (13). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/1) as a white solid (62 mg, 70%): mp: 220-222 C; H NMR (600
MHz, CDCl3) δ 7.78 (dd, J = 5.1, 2.7 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.23-7.10 (m, 5H), 6.14 (s,
1H), 5.61 (s, 1H), 5.12 (t, J = 8.4 Hz, 1H), 3.55 (d, J = 7.8 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ
170.6, 167.9, 136.5, 134.4, 131.4, 128.9, 128.7, 127.1, 123.6, 55.6, 34.9. HRMS (ESI), m/z calcd. for
C17H14N2NaO3 ([M+Na]+) 317.0897, found: 317.0890.
(S)-2-(1,3-Dioxoisoindolin-2-yl)-3-(p-tolyl)propanamide (14). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/1) as a white solid (76 mg, 85%): mp: 235-236 C; H NMR (400
MHz, CDCl3) δ 7.82-7.75 (m, 2H), 7.68-7.71 (m, 2H), 7.05-7.06 (m, 2H), 7.00-6.98 (m, 2H), 6.13 (s, 1H),
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5.67 (s, 1H), 5.12-5.07 (m, 1H), 3.51 (dd, J = 8.4, 2.4 Hz, 2H), 2.22 (s, 3H). C{1H} NMR (100 MHz,
CDCl3) δ 170.7, 167.9, 136.7, 134.4, 133.4, 131.5, 129.4, 128.7, 123.6, 55.7, 34.5, 21.0. HRMS (ESI),
m/z calcd. for C18H16N2NaO3 ([M+Na]+) 331.1053, found: 331.1021.
(1S,2S)-3-Amino-2-(1,3-dioxoisoindolin-2-yl)-3-oxo-1-phenylpropyl acetate (15). The product was
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isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (92 mg, 87%): mp: 128-130 C;
1H NMR (600 MHz, CDCl3) δ 7.73-7.71 (m, 2H), 7.67-7.64 (m, 2H), 7.35 (d, J = 7.3 Hz, 2H), 7.21-7.14
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(m, 3H), 6.75 (d, J = 10.4 Hz, 1H), 6.62 (s, 1H), 5.78 (s, 1H), 5.26 (d, J = 10.4 Hz, 1H), 2.11 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.4, 168.5, 167.3, 135.8, 134.4, 131.1, 129.1, 128.5, 127.5, 123.6,
72.6, 56.9, 21.1. HRMS (ESI), m/z calcd. for C19H16N2NaO5 ([M+Na]+) 375.0951, found: 375.0948.
(2R,3S)-2-(1,3-Dioxoisoindolin-2-yl)-3-phenyl-3-(trimethylsilyl)propanamide (16). The product
was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (80 mg, 73%): mp: 209-210
oC; 1H NMR (400 MHz, CDCl3) δ 7.67-7.58 (m, 4H), 7.20 (s, 1H), 7.06 (t, J = 7.4 Hz, 2H), 6.96-6.89 (m,
3H), 5.60 (s, 1H), 5.33 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.6 Hz, 1H), 0.06 (s, 9H). 13C{1H} NMR (150
MHz, CDCl3) δ 173.5, 170.6, 141.4, 136.2, 133.1, 130.3, 127.6, 125.4, 60.5, 39.1, 0.0. HRMS (ESI), m/z
calcd. for C20H22N2NaO3Si ([M+Na]+) 389.1292, found: 389.1290.
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(S)-3-(4-(Benzyloxy)phenyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (17).21 The product was
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isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (58 mg, 48%): mp: 150-151 C;
1H NMR (400 MHz, CDCl3) δ 7.79 (m, 2H), 7.71 (m 2H), 7.39-7.28 (m, 5H), 7.09 (d, J = 8.4 Hz, 2H),
6.80 (d, J = 8.4 Hz, 2H), 6.12 (s, 1H), 5.47 (s, 1H), 5.09 (t, J = 8.4 Hz, 1H), 4.95 (s, 2H), 3.50 (d, J = 8.4
Hz, 2H). HRMS (ESI), m/z calcd. for C24H20N2NaO4 ([M+Na]+) 423.1315, found: 423.1316.
(S)-2-(1,3-Dioxoisoindolin-2-yl)-3-(4-methoxyphenyl)propanamide (18). The product was isolated
by flash chromatography (eluent: EA/PE = 1/1) as a white solid (49 mg, 50%): mp: 185-187 oC; 1H NMR
(400 MHz, CDCl3) δ 7.79 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.09 (d, J = 8.8 Hz,
2H), 6.72 (d, J = 8.8 Hz, 2H), 6.15 (s, 1H), 5.63 (s, 1H), 5.08 (t, J = 8.6 Hz, 1H), 3.70 (s, 3H), 3.49 (d, J =
8.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 168.0, 158.5, 134.3, 131.4, 129.9, 128.4, 123.6,
114.1, 55.7, 55.2, 34.0. HRMS (ESI), m/z calcd. for C18H16N2NaO4 ([M+Na]+) 347.1002, found:
347.1000.
(S)-3-(1,3-Dioxoisoindolin-2-yl)-1-azaspiro[4.5]deca-6,9-diene-2,8-dione (19). The product was
isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (18 mg, 20%): mp: 150-151 oC;
1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 5.4, 3.0 Hz, 2H), 7.77 (dd, J = 5.6, 2.8 Hz, 2H), 7.11 (dd, J =
10.0, 3.2 Hz, 1H), 6.95 (dd, J = 10.0, 3.2 Hz, 1H), 6.37-6.23 (m, 3H), 5.18 (t, J = 10.0 Hz, 1H), 2.75 (dd,
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J = 13.4, 10.2 Hz, 1H), 2.59 (dd, J = 13.4, 9.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 184.2, 171.5,
167.3, 149.2, 148.3, 134.6, 131.7, 129.6, 128.7, 123.8, 54.5, 48.1, 35.7. HRMS (ESI), m/z calcd. for
C17H12N2NaO4 ([M+Na]+) 331.0689, found: 331.0685.
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indolo[3',2':5,6]pyrrolo[1',2':4,5][1,4]oxazino[2,3-h]quinolin-14-yl)isoindoline-1,3-dione (21). The
product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (139 mg, 74%): mp:
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219-221 C; H NMR (600 MHz, CDCl3) δ 8.97 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.93-7.90
(m, 2H), 7.92 (s, 1H), 7.78-7.76 (m, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.37 (d, J =
6.6 Hz, 3H), 7.25-7.23 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 9.0 Hz, 1H),
6.43 (d, J = 11.4 Hz, 1H), 5.35 (t, J = 10.2 Hz, 1H), 2.85-2.75 (m, 2H), 2.45 (s, 3H). 13C{1H} NMR (150
MHz, CDCl3) δ 168.2, 167.3, 151.4, 150.1, 144.9, 143.8, 140.2, 136.5, 135.6, 134.5, 131.7, 130.7, 130.5,
129.9, 127.9, 127.6, 125.2, 124.9, 124.6, 123.8, 120.3, 120.2, 117.8, 113.3, 95.6, 67.5, 48.9, 36.0, 21.7.
HRMS (ESI), m/z calcd. for C35H25N4O6S ([M+H]+) 629.1489, found: 629.1480.
Benzyl (S)-(1-amino-1-oxopropan-2-yl)carbamate (22). The product was isolated by flash
chromatography (eluent: EA/PE = 1/2) as a red solid (33 mg, 50%): mp: 157-158 oC; 1H NMR (400 MHz,
CDCl3) δ 7.40-7.30 (m, 5H), 6.09 (s, 1H), 5.53 (s, 1H), 5.36 (s, 1H), 5.11 (s, 2H), 4.32-4.21 (m, 1H), 1.40
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(d, J = 7.2 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ 143.8, 141.3, 127.8, 127.1, 125.1, 120.0, 66.9,
47.2, 28.4. HRMS (ESI), m/z calcd. for C11H14N2NaO3 ([M+Na]+) 245.0897, found: 245.0896.
(9H-Fluoren-9-yl)methyl (S)-(1-amino-1-oxopropan-2-yl)carbamate (23).22 The product was
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isolated by flash chromatography (eluent: EA/PE = 1/5) as a white solid (34 mg, 37%): mp: 187-189 C;
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H),
7.31 (t, J = 7.4 Hz, 2H), 6.05 (s, 1H), 5.66-5.52 (m, 1H), 5.42 (s, 1H), 4.52-4.38 (m, 2H), 4.35-4.15 (m,
2H), 1.40 (d, J = 5.6 Hz, 3H). HRMS (ESI), m/z calcd. for C18H18N2NaO3 ([M+Na]+) 333.1210, found:
333.1203.
(9H-Fluoren-9-yl)methyl
(S)-2-((S)-2-carbamoylpyrrolidine-1-carbonyl)pyrrolidine-1-
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carboxylate (25). The product was isolated by flash chromatography (eluent: EA/PE = 1/3) as a white
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solid (101 mg, 78%): mp: 157-159 C; H NMR (400 MHz, DMSO) δ 7.91-7.88 (m, 2H), 7.68-7.54 (m,
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3.64-3.06 (m, 5H), 2.19-2.12 (m, 1H), 2.03-1.88 (m, 4H), 1.81-1.73 (m, 2H). C{1H} NMR (150 MHz,
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DMSO) δ 174.0, 173.9, 170.4, 170.3, 154.3, 154.2, 144.5, 144.4, 144.3, 141.2, 141.2, 128.2, 128.1, 127.6,
127.5, 125.6, 125.4, 125.3, 120.6, 120.5, 66.9, 66.6, 59.9, 59.0, 58.4, 57.8, 48.7, 29.9, 29.5, 29.1, 24.9,
24.2, 23.0. HRMS (ESI), m/z calcd. for C25H27N3NaO4 ([M+Na]+) 456.1894, found: 456.1890.
(9H-Fluoren-9-yl)methyl (2-((2-amino-2-oxoethyl)amino)-2-oxoethyl)carbamate (26). The product
was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (90 mg, 85%): mp: 193-195
oC; 1H NMR (600 MHz, DMSO) δ 8.04 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.57 (s,
1H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.24 (s, 1H), 7.07 (s, 1H), 4.29 (d, J = 6.6 Hz, 2H),
13
4.24 (d, J = 6.6 Hz, 1H), 3.64 (t, J = 6.6 Hz, 4H). C{1H} NMR (150 MHz, DMSO) δ 171.3, 169.7,
157.0, 144.3, 141.2, 128.1, 127.6, 125.7, 120.6, 66.2, 47.1, 44.0, 42.3. HRMS (ESI), m/z calcd. for
C19H19N3NaO4 ([M+Na]+) 376.1268, found: 376.1265.
(9H-Fluoren-9-yl)methyl
(2-((2-amino-2-oxoethyl)(propionyloxy)amino)-2-oxoethyl)carbamate
(27). The product was isolated by flash chromatography (eluent: EA/PE = 1/1) as a white solid (110 mg,
86%): mp: 163-165 oC; 1H NMR (600 MHz, DMSO) δ 7.90 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H),
7.58 (t, J = 5.7 Hz, 1H), 7.49 (s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.08 (s, 1H), 4.32-
13
4.28 (m, 4H), 4.22-4.18 (m, 4H), 1.26-1.21 (m, 4H). C{1H} NMR (150 MHz, DMSO) δ 172.5, 169.4,
157.0, 154.0, 144.3, 141.2, 128.1, 127.6, 125.7, 120.6, 66.2, 63.4, 47.1, 46.7, 46.3, 14.4. HRMS (ESI),
m/z calcd. for C22H23N3NaO6 ([M+Na]+) 448.1479, found: 448.1473.
N-((S)-1-(((R)-1-(((S)-1-Amino-6-(1,3-dioxoisoindolin-2-yl)-1-oxohexan-2-yl)amino)-3-methyl-1-
oxobutan-2-yl)amino)-6-(1,3-dioxoisoindolin-2-yl)-1-oxohexan-2-yl)palmitamide (28). The product
was isolated by flash chromatography (eluent: EA/PE = 10/1) as a white solid (230 mg, 88%): mp: 210-
o
211 C; 1H NMR (400 MHz, CDCl3) δ 7.87-7.79 (m, 4H), 7.73 (d, J = 2.0 Hz, 4H), 6.77 (d, J = 10.0 Hz,
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1H), 6.62 (d, J = 9.2 Hz, 1H), 6.55 (s, 1H), 6.39-6.22 (m, 3H), 5.45 (s, 2H), 4.34-4.22 (m, 3H), 3.72-3.64
(m, 4H), 2.36-2.20 (m, 7H), 2.04-1.61 (m, 12H), 1.38 (s, 8H), 0.95-0.86 (m, 20H). 13C{1H} NMR (150
MHz, MeOD) δ 171.6, 168.5, 134.0, 132.0, 122.7, 67.5, 60.1, 56.9, 37.1, 35.3, 31.7, 29.8, 29.4, 29.1, 29.1,
29.0, 28.9, 27.8, 25.6, 25.1, 22.9, 22.3, 19.5, 18.5, 17.0, 16.5, 13.1. HRMS (ESI), m/z calcd. for
C49H70N6NaO8 ([M+Na]+) 893.5147, found: 893.5144.
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3-Phenylpropanamide (29). The product was isolated by flash chromatography (eluent: EA/PE = 4/1)
as a white solid (40 mg, 90%): mp: 119-121 oC; 1H NMR (400 MHz, CDCl3) δ 7.26-7.32 (m, 2H), 7.20 (d,
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J = 6.8 Hz, 3H), 5.74 (s, 1H), 5.44 (s, 1H), 2.97 (t, J = 7.8 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H). C{1H}
NMR (100 MHz, CDCl3) δ 174.7, 140.7, 128.6, 128.3, 126.3, 37.5, 31.4. HRMS (ESI), m/z calcd. for
C9H11NNaO ([M+Na]+) 172.0733, found: 172.0733.
Benzamide (30). The product was isolated by flash chromatography (eluent: EA/PE = 1/2) as a white
o
1
solid (35 mg, 95%): mp: 118-120 C; H NMR (400 MHz, CDCl3) δ 7.84-7.79 (m, 2H), 7.52 (t, J = 7.4
13
Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 6.23 (s, 2H). C{1H} NMR (150 MHz, CDCl3) δ 169.7, 133.4, 132.0,
128.6, 127.4. HRMS (ESI), m/z calcd. for C7H8NO ([M+H]+) 122.0600, found: 122.0604.
[1,1'-Biphenyl]-2-carboxamide (31). The product was isolated by flash chromatography (eluent:
o
EA/PE = 1/4) as a white solid (55 mg, 93%): mp: 158-160 C; 1H NMR (600 MHz, CDCl3) δ 7.77 (dd, J
= 7.5, 0.9 Hz, 1H), 7.50 (td, J = 7.2, 1.2 Hz, 1H), 7.45-7.41 (m, 5H), 7.41-7.38 (m, 1H), 7.36 (dd, J = 7.5,
13
0.9 Hz, 1H), 5.76 (s, 1H), 5.28 (s, 1H). C{1H} NMR (150 MHz, CDCl3) δ 171.4, 140.2, 139.9, 134.4,
130.6, 130.4, 129.1, 128.8, 128.7, 128.0, 127.6. HRMS (ESI), m/z calcd. for C13H11NNaO ([M+Na]+)
220.0733, found: 220.0731.
N-(2-Carbamoylphenyl)-4-methylbenzamide (32).23 The product was isolated by flash
o
1
chromatography (eluent: EA/PE = 1/2) as a white solid (71 mg, 93%): mp: 183-186 C; H NMR (600
MHz, MeOD) δ 8.70 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 7.9, 1.2 Hz, 1H), 7.58-
7.53 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 2.43 (s, 3H). HRMS (ESI), m/z calcd. for
C15H14N2NaO2 ([M+Na]+) 277.0947, found: 277.0942.
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(S)-2-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropanoic acid (33). The product was isolated by flash
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o
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chromatography (eluent: EA/PE = 2/1) as a white solid (82 mg, 94%): mp: 181-185 C; H NMR (400
MHz, CDCl3) δ 10.72 (s, 1H), 7.79-7.77 (m, 2H), 7.69-7.66 (m, 2H), 7.19-7.13 (m, 5H), 5.23 (t, J = 8.2
Hz, 1H), 3.60 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ 174.8, 167.4, 136.4, 134.2, 131.5,
128.8, 128.6, 127.0, 123.6, 53.1, 34.4. HRMS (ESI), m/z calcd. for C17H13NNaO4 ([M+Na]+) 318.0737,
found: 318.0735.
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(2S,3S)-3-Acetoxy-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (34). The product was
o
isolated by flash chromatography (eluent: EA/PE = 2/1) as a white solid (98 mg, 93%): mp: 141-142 C;
1H NMR (400 MHz, CDCl3) δ 7.72-7.71 (m, 2H), 7.66-7.64 (m, 2H), 7.32 (d, J = 4.4 Hz, 2H), 7.19-7.14
(m, 3H), 6.69-6.67 (m, 1H), 5.34-5.33 (m, 1H), 2.11 (s, 3H). C{1H} NMR (150 MHz, MeOD) δ 170.4,
13
167.4, 137.6, 133.9, 131.5, 127.9, 127.6, 127.3, 122.6, 74.1, 55.9, 19.9. HRMS (ESI), m/z calcd. for
C19H15NNaO6 ([M+Na]+) 376.0792, found: 376.0790.
Associated content
Supporting Information
X-ray crystallography data and CIF file of compound 21, HPLC data, 1H and 13C-NMR spectra of all new
compounds. The SI is available free of charge on the ACS Publications website.
Author information
Corresponding Author
Zhiguo Zhang: E-mail: zhangzg@htu.edu.cn
Guisheng Zhang: E-mail: zgs6668@yahoo.com
Gong Chen: E-mail: gongchen@nankai.edu.cn
ORCID
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Zhiguo Zhang: 0000-0001-6920-0471
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Guisheng Zhang: 0000-0001-9880-950X
Gong Chen: 0000-0002-5067-9889
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Author Contributions
All authors have approved the final version of this manuscript.
Acknowledgements
We thank Prof. Bingfeng Shi at Zhejiang University and Prof. Jie Wu at Fudan University for
providing selected starting materials for testing this AQ cleavage method. We thank the NSFC
(U1604285, 21772032 and 21702051), PCSIRT (IRT1061), the 111 Project (D17007), Henan
Provincial Natural Science Foundation (162300410180), Science & Technology Innovation
Talents in Universities of Henan Province (17HASTIT002), Program for Innovative Research
Team of Science and Technology in the University of Henan Province (18IRTSTHN004)
.
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