Chiral Primary Amine/Ketone Cooperative Catalysis for Asymmetric α-Hydroxylation with Hydrogen Peroxide

Article abstract of DOI:10.1021/jacs.0c11787

Carbonyls and amines are yin and yang in organocatalysis as they mutually activate and transform each other. These intrinsically reacting partners tend to condense with each other, thus depleting their individual activity when used together as cocatalysts. Though widely established in many prominent catalytic strategies, aminocatalysis and carbonyl catalysis do not coexist well, and, as such, a cooperative amine/carbonyl dual catalysis remains essentially unknown. Here we report a cooperative primary amine and ketone dual catalytic approach for the asymmetric α-hydroxylation of β-ketocarbonyls with H2O2. Besides participating in the typical enamine catalytic cycle, the chiral primary amine catalyst was found to work cooperatively with a ketone catalyst to activate H2O2 via an oxaziridine intermediate derived from an in-situ-generated ketimine. Ultimately, this enamine-oxaziridine coupling facilitated the highly controlled α-hydroxylation of several β-ketocarbonyls in excellent yield and enantioselectivity. Notably, late-stage hydroxylation for peptidyl amide or chiral esters can also be achieved with high stereoselectivity. In addition to its operational simplicity and mild conditions, this cooperative amine/ketone catalytic approach also provides a new strategy for the catalytic activation of H2O2 and expands the domain of typical amine and carbonyl catalysis to include this challenging transformation.

Full text of DOI:10.1021/jacs.0c11787

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Chiral Primary Amine/Ketone Cooperative Catalysis for Asymmetric
α‑Hydroxylation with Hydrogen Peroxide
Mao Cai, Kaini Xu, Yuze Li, Zongxiu Nie, Long Zhang,* and Sanzhong Luo*
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ABSTRACT: Carbonyls and amines are yin and yang in
organocatalysis as they mutually activate and transform each
other. These intrinsically reacting partners tend to condense with
each other, thus depleting their individual activity when used
together as cocatalysts. Though widely established in many
prominent catalytic strategies, aminocatalysis and carbonyl catalysis
do not coexist well, and, as such, a cooperative amine/carbonyl
dual catalysis remains essentially unknown. Here we report a
cooperative primary amine and ketone dual catalytic approach for
the asymmetric α-hydroxylation of β-ketocarbonyls with H2O2.
Besides participating in the typical enamine catalytic cycle, the
chiral primary amine catalyst was found to work cooperatively with a ketone catalyst to activate H2O2 via an oxaziridine intermediate
derived from an in-situ-generated ketimine. Ultimately, this enamine−oxaziridine coupling facilitated the highly controlled α-
hydroxylation of several β-ketocarbonyls in excellent yield and enantioselectivity. Notably, late-stage hydroxylation for peptidyl
amide or chiral esters can also be achieved with high stereoselectivity. In addition to its operational simplicity and mild conditions,
this cooperative amine/ketone catalytic approach also provides a new strategy for the catalytic activation of H2O2 and expands the
domain of typical amine and carbonyl catalysis to include this challenging transformation.
most active oxygen content and is relatively safe and easy to
handle with water as the sole byproduct.7 Enantioselective C−
H hydroxylation with H2O2 is arguably one of the most
straightforward and atom-economic oxidation strategies in
accessing chiral alcohols. However, achieving catalytic
asymmetric hydroxylation with hydrogen peroxide remains a
great challenge, and successful examples along this line are
extremely scarce.8 To modulate the activity and stereo-
selectivity under mild conditions, catalytic activation of H2O2
into more electrophilic oxygen species is required because
H2O2 itself is not electrophilic enough and can even serve as a
good nucleophile under neutral and basic conditions.9 Aside
from the established metal-mediated activation strate-
gies,7d,8b,10 there recently appeared organocatalytic strategies
that proceeded via dioxarine, oxaziridine, or perhydrate
intermediates using either ketone or imine catalysts (Figure
1b).5,11 To date, no enantioselective version has been
developed. Herein, we report the application of ketone
catalysis in the asymmetric enamine-based α-hydroxylation
INTRODUCTION
■
Aminocatalysis is a fundamental activation mode in the
transformations of carbonyl compounds. This catalysis has
become a prevalent and enabling strategy for α- or β-
functionalizations of carbonyls via enamine or iminium ion
activation (Figure 1a).1 On the other hand, carbonyl catalysis
has recently appeared as a viable approach for the α-
functionalization of glycine-type amines.2 Like its amine
counterpart, carbonyl catalysis also has its biological origin in
nature’s enzymes, the pyridoxal-dependent aldolases.3 Its early
successes can be traced back to before the renaissance of
organocatalysis when chiral ketone or ketimine catalysts were
extensively explored as metal-free oxidation catalysts.4 In these
cases, the carbonyl catalysts promoted concerted O/N atom
transfer with olefins via dioxarine or oxaziridine intermediates,
and similar catalysts have been recently used in C−H insertion
reactions of alkanes.5,6 Most of such ketone/aldehyde catalysts
bear reactive carbonyls with electron-withdrawing substituents
and would readily couple with nucleophilic amines. Hence, as
inherent reacting partners, amines and ketone/aldehyde
carbonyls are mutually exclusive for targeted catalytic trans-
formations from a mechanistic point of view, like a yin−yang
interplay. Cooperative amine and carbonyl dual catalysis
remains essentially unknown.
Received: November 10, 2020
Published: January 5, 2021
Widely applied in industry and environmental protection as
a green terminal oxidant, hydrogen peroxide is considered to
be an ideal oxygen source for chemical synthesis as it has the
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© 2021 American Chemical Society
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Figure 1. Organocatalytic activation of hydrogen peroxide. (a) Typical activation modes in aminocatalysis and carbonyl catalysis. (b) Active
intermediates in the organocatalytic activation of H2O2. (c) Our concepts of amine and carbonyl dual catalysis: The chiral iminium ion generated in
situ by primary amine and ketone catalysts activates H2O2 in the form of chiral oxaziridine, which couples with enamine, also derived from amine
catalysts, to afford α-hydroxylation product 2a. (d) Kinetic profiles of ketone catalysis in the reaction of 1a.
a b c d
, , ,
Table 1. Identification of the Amine/Ketone Dual Catalysis and Optimization
a
Standard reaction condition: 1a (0.2 mmol), chiral amine 3a/NHTf2 (20 mol %), PhCOCF3 (20 mol %), and H2O2 (30 wt % in water, 0.3 mmol)
b
in 0.5 mL PhMe/DCE (1/1) at room temperature in air for 3 h. The yield was determined by GC analysis using 1,3,5-trimethoxybenzene as an
internal standard. The ee value was determined by HPLC analysis. Yield of product isolated for 4 h.
c
d
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a b c d
, , ,
Table 2. Substrate Scope of Amine/Ketone Dual Catalysis
a
Condition A: Reactions were performed with 1 or 5 (0.2 mmol), 3a/Tf2NH (20 mol %), PhCOCF3 (20 mol %), and H2O2 (30 wt % in water, 0.3
mmol) in 0.5 mL of PhMe/DCE (1/1) at room temperature in air for 4 h. Yield of isolated product. The ee values were determined by HPLC
b
c
analysis. The reaction was performed on the scale of 0.1 mmol. Condition B: Reactions were performed with 1 or 5 (0.2 mmol), 3a/Tf2NH (20
d
mol %), H2O2 (30 wt % in water, 0.3 mmol), and Na2SO4 (1.0 equiv) in 0.5 mL of PhMe/DCE (1/1) at room temperature in air for 48 h. 40 °C.
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Figure 2. Synthesis application. Conditions: (a) NaBH(OAc)3 (1.0 equiv), HOAc (5 mol %), DCM, 0 °C, 30 min. (b) ZnCl2 (1.0 equiv), NaBH4
(1.0 equiv), THF, −40 °C, 30 min. (c) Propionic anhydride (1.0 equiv), DMAP (10 mol %), Et3N (1.0 equiv).
Figure 3. (a) Possible oxidative intermediates for the ketone pathway (left) and ketimine pathway (right). (b) 18O-labeling experiments by H218O.
The possible labeling pathways are listed on the left, with experimental observations shown on the right. The only pathway leading to doubly
labeled product 18O2-2a was through a dioxirane intermediate, 18O-II′, and the absence of 18O2-2a suggested that this was unlikely. UHP: urea
hydrogen peroxide. (c) Control experiment with 4d as a catalyst. Conditions: 1a (0.2 mmol), 3a/Tf2NH (20 mol %), 4d (20 mol %), and H2O2
(30 wt % in water, 0.3 mmol) in 0.5 mL of PhMe/DCE (1/1) at room temperature in air for 3 h. (d) Control experiment with preformed
oxaziridine 4e as the oxidant. Conditions: 1a (0.2 mmol), 3a/Tf2NH (20 mol %), and oxaziridine 4e (0.30 mmol) in 0.5 mL of PhMe/DCE (1/1)
at room temperature in air for 3 h.
with hydrogen peroxide. Though enamine-based α-oxygen-
ation has been extensively explored, successful examples have
relied on preactivated reagents such as oxaziridines, nitro-
sobenzenes, benzoyl peroxide, and singlet oxygen.12 Direct
catalytic enamine hydroxylation with hydrogen peroxide has
not been achieved.13 Though Ooi has reported an enolate-
based asymmetric α-hydroxylation with hydrogen peroxide, the
reaction unfortunately required stoichiometric trichloro-
acetonitrile as an activating reagent.14 Similar reactions have
also been examined with chiral Lewis base catalysis but with
moderate enantioselectivity and limited scope.15
stereocontrol not obtainable by other methods. Our joint
amine/ketone catalytic protocol could be applied in the late-
stage hydroxylation reaction of complex molecules. Mecha-
nistic studies revealed that the reaction proceeded via
enamine−oxaziridine coupling derived from the two working
catalysts and that both amine and ketone catalysts participated
in the activation of hydrogen peroxide via an iminium ion
intermediate (Figure 1c).
RESULTS AND DISCUSSION
■
Catalyst Screening and Reaction Development. In our
initial studies, we investigated the enantioselective hydrox-
ylation of β-ketoester 1a with primary amine catalysts
developed previously by our group. Among the different
In our strategy (Figure 1c), the chiral primary amine catalyst
worked in concert with a ketone catalyst to promote the
effective α-hydroxylation of β-ketocarbonyls with excellent
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Figure 4. (a) nESI(+)-MS spectrum of the reaction of 3a/NHTf2, 4c, and H2O2 (30 wt % in water) in DCE/PhMe in situ. (b) CID analysis of
oxaziridine intermediate IV′.
primary amine catalysts screened, primary−secondary dia-
mines such as 3a were identified as the preferred amine
catalyst. The reaction with only amine catalyst (e.g., 3a/
Tf2NH) was sluggish, requiring at least 48 h for complete
conversion (Table 1, entry 3). At this point, the addition of a
ketone catalyst was found to significantly enhance the reaction
rate, and the optimal 3a/4a combination led to a nearly 10
times faster reaction (Figure 1d). The reaction now had an
85% yield and a 96% ee in 3 h (Table 1, entry 1). Aldehydes
such as benzaldehyde were found to totally inhibit the reaction
(Table 1, entry 9), and the smallest ketone, acetone, showed
diminished activity while maintaining enantioselectivity (Table
1, entry 10). Electron-withdrawing substitutions on the ketone
carbonyl are critical to activity (Table 1, entries 11−13), and
both CF3 (4a or trifluoroacetone) and carboxylate (4c)
substituted ketones showed good activity with similar
enantioselectivity. The primary−secondary diamine motif
(e.g., 3a−3c) was critical to the joint catalysis as the reaction
with tertiary amine (3d) showed rather low activity and
enantioselectivity (Table 1, entries 14−16). In a control
experiment, no reaction was observed in the absence of amine
catalyst (Table 1, entry 2), pinpointing the decisive role of
aminocatalysis in the reaction. Consistent with the well-known
role of Brønsted acids facilitating aminocatalysis, the use of a
strong acid additive such as Tf2NH is essential for both the
activity and enantioselectivity (Table 1, entry 4).
activity but without any selectivity (Table 1, entry 6). These
results indicate that the current amine/ketone dual catalysis
preferentially activates H2O2 to facilitate the subsequent
hydroxylation.
Substrate Scope. As shown in Table 2, different ester
groups of acetoacetates were well tolerated (Table 2, entries
1−8). A variety of α-alkyl substituents including methyl, ethyl,
decanyl, and benzyl all worked well to give the expected
hydroxylation products in 70−94% yields and 96−98% ee
(entries 9−13). Functional groups such as cyano (2n), ester
(2o, 2p), ketone (2q), acetal (2r), alkenyl (2s), and alkynyl
(2t) at the α-position were equally applicable (entries 14−20).
An ethyl ketone (2u) is also workable with a 59% yield and
96% ee (entry 21). Cyclic ketoesters exhibited divergent
behavior, smaller rings (n = 4, 5, 6) such as cyclopentanone
and cyclohexanone did not show the expected reactivity,16 and
the larger cyclic ketoesters (n = 7, 12) reacted smoothly to give
the desired products in high enantioselectivity with slightly
diminished reactivity (entries 22−25). A gram-scale hydrox-
ylation reaction of β-ketoester 1a was performed to probe the
practicability with 10 mol % catalyst loading, and comparable
values of the isolated yield and enantioselectivity were
obtained in 8 h (Table 2, entry 1).
β-Ketoamides are versatile structural motifs in biologically
active compounds,17 and their direct oxidative transformations
are challenging because of their oxidative compatibility.18 It
was found that β-ketoamides worked extremely well under our
dual catalytic conditions. Both aryl and alkyl amides could be
incorporated to give the expected hydroxylation adducts with
93−99% ee (entries 26−33). Aryl amides bearing either an
Other oxidants have also been examined in the dual catalytic
system (Table 1, entries 5−8). Commonly employed oxidants
such as t-butyl peroxide, oxone, and air (or pure molecular
oxygen) were virtually inactive, and m-CPBA showed some
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Figure 5. (a−d) Kinetic order plots for 1a, H2O2, 3a, and 4a, respectively. (a) Plot of initial rate against [1a] (from 0.35 to 0.55 M in DCE/PhMe).
(b) [H2O2] (from 0.3 to 0.6 M in DCE/PhMe). (c) [3a] (from 0.02 to 0.08 M in DCE/PhMe). (d) [4a] (from 0.01 to 0.08 M in DCE/PhMe).
(e) Plot of enantiomeric excess of 2a against the enantiomeric excess of 3a, showing the existence of a negative nonlinear effect (NLE). (f) Two-
catalyst model for the negative NLE with heterocombinations R/S and S/R reacting faster than homocombinations R/R and S/S, attenuating the
enantioselectivity. (g) Proposed catalytic cycle of synergetic catalysis of primary amine 3a and PhCOCF3 4a.
electron-donating group (6b), electron-withdrawing groups
(6c−e), or a steric ortho substituent (6g) were equally
applicable. Alkyl substituents at either the α- or α′-position of
ketoamides were well tolerated (entries 34−36). Cyclic
ketoamides also worked well in the reactions to give the
desired products in 55−87% yields and 90−98% ee (entries
37−39). Meanwhile, the reaction outcomes in the absence of a
ketone catalyst (Table 2, condition B) were also listed for
comparison, exhibiting generally lower yields and longer
reaction time. These observations further highlight the catalytic
power of this dual catalytic system.
We also challenged the current protocol in the late-stage
hydroxylation of structurally complexed substrates bearing
existing chiral centers. In this regard, it was shown that the
hydroxylation was solely catalyst-controlled to give the
expected diastereoisomers with high diastereoselectivity
(entry 40 vs entry 41, entry 45 vs entry 46). Peptidyl amide
(6q) or nopyl (6r) and menthyl esters (6s) worked smoothly.
The catalysis also worked with a cholesteryl ester (6t and 6u)
with reasonably good activity and high diastereoselectivity
(entries 45 and 46).
The obtained α-hydroxy β-oxo skeletons are prevalent
structural motifs in natural products and pharmaceuticals and
could also serve as valuable synthons for synthetic trans-
formations.19 The vicinal diol moiety of macrolide antibiotics
(e.g., pikromycin) inspired us to pursue a concise synthesis
path to assemble the fragment.20 Key intermediate 2t could be
synthesized by the developed catalytic asymmetric hydrox-
ylation, and reduction of the keto moiety of 2t followed by
chemoselective acylation afforded the desired 1,2-anti-diol
fragment, 9a. Changing the reducing condition led to a
reversed configuration of 1,2-diol, producing 1,2-syn-diol 9b
(Figure 2), which is also a versatile synthon in natural product
synthesis.21
Mechanism Studies. To account for the dramatic
promoting effect of 4a, a H2O2-activation mechanism was
invoked. As known, the organocatalytic activation of H2O2 may
proceed via ketone mode with a dioxirane intermediate (II,
derived from I, Figure 3a) or ketimine mode with an
oxaziridine intermediate (IV, derived from III, Figure 3a).
18O-labeling studies with H218O-UHP were conducted. In this
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Figure 6. DFT-calculated free-energy profiles of the activation of hydrogen peroxide and formation of enamine and the key TSs for the
hydroxylation step.
case, ketone 4c, with catalytic performance similar to that of 4a
(Table 1, entry 1 vs 13), was used for the convenience of ESI-
MS detection. Under the bifunctional influence of amine-
Brønsted acid conjugate 3a/Tf2NH, the carbonyl oxygen
underwent a fast isotope swap with H218O, and the double
18O-labeling product on both the carbonyl-O and α-hydroxyl-
O would be formed if the reaction followed the dioxirane-II
pathway (Figure 3b). However, such a doubly labeled product
was not detected by in situ HRMS analysis. In addition, the
control experiment indicated that preformed imine such as 4d
could effectively promote the reaction with 47% yield and 95%
ee (Figure 3c). The reaction with a prepared oxaziridine, 4e,
worked well to give the expected adduct with comparable
enantioselectivity (Figure 3d). Taken together, these results
suggest that the reaction preferentially proceeds via the
ketimine pathway with III or IV. The ketone pathway via I
or II, even if not entirely excluded, should be neglectable
because dioxirane formation between ketone and H2O2
normally requires either strongly acidic or strongly basic
conditions.4 Additionally, amine−ketone coupling would be
favored over the perhydroxylation of ketone under the present
acid−base bifunctional conditions. Nano-ESI-MS analysis of
the reaction mixture led to the identification of expected
iminium ion intermediate 9b and oxaziridine intermediate IV′
(Figure 4a), and the structure of IV′ was further established by
collision-induced dissociation analysis (Figure 4b), adding
direct evidence to a ketimine mechanism.
the dual catalytic system was also determined, and a minor
negative NLE was clearly noted (Figure 5e). Previously,
negative NLE was reported in proline-catalyzed Robinson
annulation by Agami;22 however, the existence of NLE in this
reaction was later disapproved by List and Houk.23 The
observation of (−)-NLE in our reaction suggests that the
stereodetermining step is not a one-catalyst system. An
enamine−oxaziridine coupling involving two molecules of
chiral aminocatalysts can be proposed to account for the NLE
(Figure 5f). A similar two-catalyst mode has been proposed by
Kagan and Agami.22 According to this model, the catalysis with
the hetero-R/S and S/R combination is favored over that with
the homo-R/R or S/S combination in the stereogenic step,
hence leading to attenuation of the overall enantioselectivity.
On these bases, a dual catalytic pathway involving an enamine
cycle and a ketimine cycle was proposed as shown in Figure 5g.
In this coupled cycle, ketimine formation from 3a and 4a is the
rate-limiting step, and the effective coupling between enamine
10 and intermediate III or IV leads to the hydroxylated adduct
in high stereoselectivity. It is noted that the chirality of
oxaziridine intermediate IV′ may also contribute to the
stereocontrol.24 However, the observation of significant
enantioselectivity with a racemic oxaziridine 4e (Figure 3d)
suggested that the chiral effect of IV should be minor, and the
chiral induction was mainly determined by the enamine
intermediate.
We further verified the reaction profile by DFT calculations
(Figure 6, see Supporting Information Section 9 for details).
Both enamine (Int3) and ketimine (Int5) formation followed
a bifunctional mode with the protonated secondary amine
serving as the acid catalytic moiety, characteristic of diamine
Brønsted acid catalysis as known.25 In these coupled cycles,
aminocatalyst 3a/NHTf2 played a dual role in reacting with
either ketoester 1a or ketone catalyst 4a to form the key
The kinetics were determined by measuring the initial rates
with a varying concentration of H2O2, substrate, or catalysts
(Supporting Information, Section 8). The reaction was found
to be zeroth order in either substrate 1a or H2O2 (Figure 5a,b)
and first order in both amine and ketone catalysts (Figure
5c,d). A rate-limiting state preceded the C−O bond formation,
in line with this kinetic scenario. The nonlinear effect (NLE) of
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enamine (Int3) and oxaziridine (IV) intermediates, respec-
tively. Ketalization with 4a or 1a is a quickly equilibrated
processes, and the subsequent dehydration of ketal Int4 is
much more endergonic than that for Int1, making the former
an overall rate-limiting step with an energy barrier of 20.9 kcal/
mol. The downhill reketalization of Int5 with hydrogen
peroxide is quite facile to give expected perhydroxyl acetal III
and oxaziridine IV. The conversion of III to IV occurred
spontaneously with no obvious barrier. Both III and IV could
effectively couple with enamine intermediate Int3 to give the
R-selective product via TS9 (Supporting Information Figure 5)
and TS7, respectively. The minor S product was formed by the
E-enamine addition to IV, with a calculated 99% ee value,
which is in accordance with the experimental result. In TS7,
intermolecular N−H−N hydrogen bonding between two
secondary amine side chains was noted, facilitating the
alignment of the two reactive intermediates. Depending on
the ionic status of the two intermediates, anion-mediated H-
bonding may also contributed and such a ternary TS8 could
also be located, showing a slightly favored energy barrier of
18.4 kcal/mol (Figure 6).26
AUTHOR INFORMATION
Corresponding Authors
■
Long Zhang − Center of Basic Molecular Science, Department
of Chemistry, Tsinghua University, Beijing 100084, China;
Email: zhanglong@tsinghua.edu.cn
Sanzhong Luo − Beijing National Laboratory for Molecular
Sciences, Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China; Center of Basic Molecular
Science, Department of Chemistry, Tsinghua University,
Beijing 100084, China; orcid.org/0000-0001-8714-
4047; Email: luosz@tsinghua.edu.cn
Authors
Mao Cai − Beijing National Laboratory for Molecular
Sciences, Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China; School of Chemical Science,
University of Chinese Academy of Sciences, Beijing 100049,
China
Kaini Xu − Center of Basic Molecular Science, Department of
Chemistry, Tsinghua University, Beijing 100084, China
Yuze Li − School of Chemical Science, University of Chinese
Academy of Sciences, Beijing 100049, China; Beijing
National Laboratory for Molecular Sciences, Key Laboratory
for Analytical Chemistry for Living Biosystems, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190,
China
Zongxiu Nie − School of Chemical Science, University of
Chinese Academy of Sciences, Beijing 100049, China; Beijing
National Laboratory for Molecular Sciences, Key Laboratory
for Analytical Chemistry for Living Biosystems, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190,
China; orcid.org/0000-0001-8514-6348
CONCLUSIONS
■
We have shown that amine and ketone can work in concert to
promote the effective enantioselective transformation of
carbonyls. Dual amine and ketone catalysis enable the
electrophilic activation of H2O2 via in-situ-generated ketimine
in the form of oxaziridine and allows for its effective coupling
with a nucleophilic enamine intermediate. The developed dual
organocatalytic protocol demonstrated high activity and
enantioselectivity for a broad range of β-ketoeasters andβ-
ketoamides that are not possible with other catalytic
approaches. The current approach represents a new organo-
catalytic strategy in activating hydrogen peroxide. Given its
versatility and operational simplicity, further advances along
this line can be anticipated.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11787
METHODS
Notes
■
The authors declare no competing financial interest.
Here we describe the general procedures for the α-hydroxylation of
carbonyl compounds through dual amine and ketone catalysis.
General procedure for the conditions: An oven-dried tube
equipped with stir bar was charged with the corresponding β-
ketocarbonyls (1, 0.2 mmol) and aminocatalyst 3a/NHTf2 (20 mol
%). After dissolution in a mixed solvent of toluene and 1,2-
dichloroethane (0.5 mL, 1:1 v/v), trifluoroacetophenone 4a (20
mol %) was added to the vial. Then H2O2 (30 wt % in water, 0.3
mmol) was added via a syringe. Upon completion of the addition, the
reaction was stirred at room temperature for at least 4 h (TLC
analysis). The solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography (petroleum ether/
ethyl acetate = 20:1−4:1) to afford desired product 2 or 6. The
enantiomeric excess was determined by HPLC.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China
(21672217, 21861132003, and 22031006) and the Tsinghua
University Initiative Scientific Research Program for financial
support. We thank the Tsinghua Xuetang Talents Program for
computational support. S.L. is supported by the National
Program of Top-Notch Young Professionals. We thank
Professor Xinhao Zhang and Heming Jiang from the Peking
University Shenzhen Graduate School for assistance with ESI-
MS studies. All of the data supporting the findings of this study
are available within the paper and its
Supporting Information files,
.
The data sets generated and analyzed during the current study
are available from the corresponding author on reasonable
request.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11787.
■
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