Organocatalytic Enantioselective γ-Elimination: Applications in the Preparation of Chiral Peroxides and Epoxides

Article abstract of DOI:10.1021/acs.orglett.0c00295

An organocatalyzed enantioselective γ-elimination process has been achieved and applied in the kinetic resolution of peroxides to access chiral peroxides and epoxides. The reaction provided a pathway for the preparation of two useful synthetic and biologically important structural motifs through a single-step reaction. A range of substrates has been resolved with a selectivity factor up to 63. The obtained enantioenriched peroxides and epoxides allowed a series of transformations with retained optical purities.

Full text of DOI:10.1021/acs.orglett.0c00295

pubs.acs.org/OrgLett
Letter
Organocatalytic Enantioselective γ‑Elimination: Applications in the
Preparation of Chiral Peroxides and Epoxides
Fangli Hu, Zhili Chen, Yu Tan, Da Xu, Shengli Huang, Shiqi Jia, Xiangnan Gong, Wenling Qin,*
and Hailong Yan*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00295
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An organocatalyzed enantioselective γ-elimination process has been achieved and applied in the kinetic resolution of
peroxides to access chiral peroxides and epoxides. The reaction provided a pathway for the preparation of two useful synthetic and
biologically important structural motifs through a single-step reaction. A range of substrates has been resolved with a selectivity
factor up to 63. The obtained enantioenriched peroxides and epoxides allowed a series of transformations with retained optical
purities.
limination reactions1 represent a direct and versatile
Scheme 1. Previous Work and Our Strategy
2
Estrategy for the construction of new carbon−carbon or
carbon−heteroatom bonds3 with molecular complexities.
Enantioselective elimination processes4 are of particular
interest due to their convenience in accessing valuable chiral
compounds, albeit asymmetric elimination approaches have
not become a well-established methodology in the organic
chemist’s toolbox. As a precedent example, enantioselective β-
hydride elimination has been achieved to access enantioen-
riched allenes by using Pd(II)−chiral ligands as the catalytic
system.5 As shown in Scheme 1a, our group has developed
some organocatalytic enantioselective β-elimination reactions
based on β-functionalized ketones to access chiral sulfones and
compounds with contiguous halides bearing stereocenters via
kinetic resolution.6 Despite these achievements, an inherent
drawback of kinetic resolution based on β-elimination is that
the products of the β-elimination reaction are usually achiral
substances. Theoretically, by extending the distance between
the leaving group and the carbonyl to carry out a γ-
elimination,7 followed by an α-H sponge in the presence of
chiral catalyst, the enantioselective cyclization can be realized
to give an enantioenriched three-membered ring8 as the
product, and the chiral substrate can be recovered (Scheme
1b). To our surprise, this strategy has never been reported,
probably because the large distance between the leaving group
and the carbonyl functionality increased the difficulty of
stereocontrol.
Received: January 21, 2020
In our efforts to develop enantioselective elimination
processes, we were encouraged to design a new reaction
https://dx.doi.org/10.1021/acs.orglett.0c00295
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 1. Optimization of Reaction Conditions
b
b
c
d
s
entry
cat.
solvent
toluene
toluene
toluene
toluene
toluene
m-xylene
p-xylene
mesitylene
CH2Cl2
CHCl3
ethyl acetate
THF
acetone
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
concentration (M) (T (°C))
ee (1a) (%)
ee (2a) (%)
conv. (%)
1
2
3
4
5
6
7
8
A
B
C
D
E
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.1 (25)
0.2 (25)
0.13 (25)
0.07 (25)
0.05 (25)
0.07 (0)
0.07 (15)
0.07 (35)
90
64
−32
51
9
75
55
83
50
30
32
6
27
96
92
94
72
13
63
82
87
−83
87
39
86
90
86
89
91
84
78
80
78
81
84
88
85
87
71
52
42
28
37
19
47
38
49
36
25
28
7
25
55
53
53
45
13
42
52
31
28
15
24
2
30
33
34
28
28
16
9
12
31
31
40
34
14
27
13
9
10
11
12
13
14
15
16
17
18
19
20
77
a
b
Reaction conditions: ( )-1a (0.1 mmol) and catalyst (10 mol %) in solvent for 47 h. ee value was determined by HPLC analysis on a chiral
c
d
stationary phase. Conversion = (ee1a)/(ee1a + ee2a). Selectivity factor was calculated by the method of Fiaud: s = ln[(1 − conv.)(1 − ee1a)]/ln[(1
− conv.)(1 + ee1a).
model involving γ-elimination with a Brønsted base organo-
catalyst. In 2011, Li9 reported an iron-catalyzed direct
carbonylation−peroxidation of alkenes to access peroxides,
which was demonstrated to undergo an epoxidation process to
furnish the corresponding epoxides in the presence of an
organo-base catalyst.9a We envisioned that a chiral organo-
catalyst might be used to carry out the reaction enantiose-
lectivity, in which a kinetic resolution procedure for preparing
two kinds of chiral molecules based on γ-elimination could be
realized.
Both peroxide and epoxide motifs exist in a large number of
biologically interesting natural products as well as drugs10 and
were considered to be responsible for their bioactivities, such
as anticancer,11 antiparasite,12 antibacterial,13 and antiaging
activities. In the past decades, tremendous progress has been
made in the asymmetric preparation of chiral epoxides.14
Meanwhile, direct enantioselective peroxidation processes have
received considerable attention, and pioneering works have
been reported by Deng,15 Nakamura,16 Li,17 and Dussault.18
Despite these achievements, the enantioselective approaches
toward the preparation of chiral peroxides and epoxides in one
single step still remain unexplored. We reported herein the first
organocatalyzed19 enantioselective kinetic resolution approach
to access chiral peroxides via an enantioselective γ-elimination
process and afford chiral epoxides as valuable products.
We began our study by using racemic peroxide 1a as the
substrate in the presence of quinine-derived thiourea catalyst A
in toluene. To our delight, the reaction proceeded smoothly in
52% conversion, and the epoxide (2R,3S)-2a was obtained
with 82% ee and the chiral peroxide (S)-1a was recovered with
90% ee (Table 1, entry 1). Next, the Takemoto catalyst
(catalyst B) was tested under the same reaction conditions.
The enantiopurity of the epoxide was increased, albeit the ee
value of substrate was decreased (Table 1, entry 2).
Cinchonine-derived thiourea catalyst C was not able to
increase the enantiopurity of the product and the substrate,
thus giving the lower s value for this resolution reaction based
on γ-elimination (s = 15, Table 1, entry 3). To improve the
performance of this resolution process, we further evaluated
quinine-derived squaramide catalysts D and E. Disappoint-
ingly, both catalysts turned out to be inferior for enantiocon-
trol (Table 1, entries 4 and 5). After the optimal catalyst was
identified, we evaluated a series of solvents (Table1, entries 6−
13), and mesitylene was demonstrated to be the best solvent
for this enantioselective γ-elimination reaction (s = 34, Table 1,
entry 8). The further evaluation of the concentration (Table 1,
entries 14−17) and temperature (Table 1, entries 18−20)
B
https://dx.doi.org/10.1021/acs.orglett.0c00295
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 2. Substrate Scope
a
Reaction conditions: ( )-1 (0.1 mmol), A (10 mol %) in mesitylene (1.5 mL) at 25 °C. See the SI for the reaction time. The ee value was
determined by HPLC analysis on a chiral stationary phase. Yield of isolated product. Conversion = (ee1)/(ee1 + ee2). The diastereomeric ratio (dr)
was determined by the 1H NMR analysis of the crude reaction mixture. The selectivity factor was calculated by the method of Fiaud: s = ln[(1 −
conv.)(1 − ee1)]/ln[(1 − conv.) (1 + ee1)].
C
https://dx.doi.org/10.1021/acs.orglett.0c00295
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
suggested that the highest s value could be obtained under the
following reaction conditions: 0.1 mmol substrates and 10 mol
% catalyst A in mesitylene (1.5 mL) at 25 °C for 47 h.
Scheme 3. Gram-Scale Preparation and Synthetic
Applications
a
With the optimized reaction conditions in hand (Table 1,
entry 16), we investigated the substrate scope of the
established kinetic resolution of peroxides through an
enantioselective γ-elimination reaction (Scheme 2). The
peroxides were obtained from the corresponding olefins,
aldehydes, and t-BuOOH or cumyl hydroperoxide under the
catalysis of n-Bu4NBr; the detailed procedures are shown in the
SI. Substrates with electron-donating R1 groups at the phenyl
ring allowed the enantioselective γ-elimination to give chiral
peroxides (S)-1b−f with high s values and with up to 94% ee;
the corresponding epoxides (2R,3S)-2b−f were also obtained
with good enantioselectivities. para-Chloride-substituted sub-
strate racemic 1g was tolerated in our reaction system, and
chiral peroxide (S)-1g was recovered in 44% yield with 90% ee.
Epoxide (2R,3S)-2g was formed with a moderate ee value.
Similarly, para-bromo-substituted substrate 1h also afforded a
good selectivity with an s value of 31. By substituting the
phenyl ring with naphthalene, 2-furan, or 2-thiophene,
peroxides 1i−k were also efficiently resolved with high
enantioselectivities (s value up to 42). After the investigation
of the R1 group of peroxides, we determined the substrate
scope with different R2 groups. Substrates with electron-
donating R2 groups resulted in chiral peroxides (S)-1l (methyl)
and (S)-1m (tert-butyl), respectively, with 98% ee and 93% ee,
and epoxides (2R,3S)-2l and (2R,3S)-2m were obtained with
good enantioselectivities as well. Using halides such as fluoride,
chloride, and bromide as R2 groups located in the para position
of phenyl ring, corresponding substrates were suitable for the
resolution to give enantioenriched peroxides (S)-1n−p (up to
97% ee) and epoxides (2R,3S)-2n−p (up to 84% ee), and
selectivity factors as high as 37 were obtained. The absolute
configurations of (S)-1p and (2R,3S)-2p were determined by
X-ray crystallography, and others were analogously assigned.
When R2 was an ortho-chloro or meta-bromo group on the
phenyl ring, chiral peroxides (S)-1q and (S)-1r were recovered
after an enantioselective γ-elimination process with promising
results (96% ee and up to 42% yield), and epoxides (2R,3S)-
2q-r were obtained with up to 81% ee. After substituting the
tert-butyl peroxide group with a dimethyl phenyl group, the
corresponding substrate could also be resolved to give chiral
peroxide (S)-1s in 41% yield with 87% ee. Nevertheless, the
reactions were not successful with α-ester peroxide and alkyl
ketone peroxides under standard reaction conditions.
a
For reaction conditions, see the SI.
both products were obtained in good yield with high ee.
Treating epoxide (2R,3S)-2p with SnCl4 afforded a chlorinated
open-chain product 6 instead of a cyclized adduct, as
reported.20 The absolute configuration of product 6 was
assigned through X-ray crystallography.
In an attempt to gain some insights into the mechanism of
this enantioselective γ-elimination transformation, we meas-
ured the independent initial rates of parallel reactions with
substrates ( )-1p and α-proton-deuterated substrate ( )-1p-
D under the standard reaction conditions (Scheme 4). The
primary intermolecular kinetic isotopic effect (KIE)21 was
calculated to be 2.88, indicating that the deprotonation of the
α-proton of the carbonyl group was probably involved in the
rate-determining step.
a
Scheme 4. Kinetic Isotopic Effect Experiment
After the substrate scope of the reaction was investigated, we
planned to further demonstrate the synthetic potential of our
reaction. First, a gram-scale reaction was carried out to prepare
(S)-1p and (2R,3S)-2p under the optimal reaction conditions,
and the chemical yield and enantioselectivity showed almost
no variation (Scheme 3). Next, a few functional trans-
formations of chiral substrates and products were conducted.
As expected, the enantioenriched peroxide (S)-1p could be
converted into the corresponding peroxide 3 in 80% yield with
good stereoselectivity (93% ee and 4:1 dr) by sodium
borohydride. Upon the treatment of (S)-1p with 2,4-
dinitrophenyl hydrazine in methanol at 40 °C for 6 h, product
4a was formed as the major product in 73% yield with 93% ee
value. Moreover, the utility of the epoxide from this γ-
elimination-based kinetic resolution was also explored. Epoxide
(2R,3S)-2p was sufficiently transformed into alcohol 5 and
ester 7 through a reductive and oxidative process, respectively;
a
For reaction conditions, see the SI.
D
https://dx.doi.org/10.1021/acs.orglett.0c00295
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
In summary, we established the first organocatalytic kinetic
resolution of peroxides through enantioselective γ-elimination
to afford chiral peroxides and epoxides. Both substances are
important building blocks in synthetic chemistry and play
reliable roles in numerous bioactive natural products as well as
medicines. This methodology provided a single-step reaction
for the preparation of two kinds of valuable chiral compounds.
This asymmetric γ-elimination-based resolution process was
tolerant of a range of peroxides with high selectivity factors,
and the obtained products allowed a variety of further
transformations while retaining optical purity. Furthermore,
the KIE study suggested that the deprotonation of the α-
proton of the carbonyl group determined the rate of this
enantioselective γ-elimination process.
Xiangnan Gong − Analytical and Testing Center of Chongqing
University, Chongqing University, Chongqing 401331, P. R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00295
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the Scientific Research
Foundation of China (grant nos. 21772018, 21922101, and
21901026).
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00295.
■
■
(1) (a) Fumagalli, G.; Stanton, S.; Bower, J. F. Recent Method-
ologies that Exploit C-C Single-Bond Cleavage of Strained Ring
Systems by Transition Metal Complexes. Chem. Rev. 2017, 117,
9404−9432. (b) Chu, T.; Nikonov, G. I. Oxidative Addition and
Reductive Elimination at Main-Group Element Centers. Chem. Rev.
2018, 118, 3608−3680.
(2) (a) Huang, Y.; Hayashi, T. Rhodium-Catalyzed Asymmetric
Arylation/Defluorination of 1-(Trifluoromethyl)alkenes Forming
Enantioenriched 1,1-Difluoroalkenes. J. Am. Chem. Soc. 2016, 138,
12340−12343. (b) Liao, G.; Li, B.; Chen, H.-M.; Yao, Q.-J.; Xia, Y.-
N.; Luo, J.; Shi, B.-F. Pd-Catalyzed Atroposelective C-H Allylation
through β-O Elimination: Diverse Synthesis of Axially Chiral Biaryls.
Angew. Chem., Int. Ed. 2018, 57, 17151−17155.
(3) (a) Liu, D.; Kozmin, S. A. Catalytic Enantioselective Isomer-
ization of Silacyclopentene Oxides: New Strategy for Stereocontrolled
Assembly of Acyclic Polyols. Angew. Chem., Int. Ed. 2001, 40, 4757−
4759. (b) Igawa, K.; Yoshihiro, D.; Abe, Y.; Tomooka, K.
Enantioselective Synthesis of Silacyclopentanes. Angew. Chem., Int.
Ed. 2016, 55, 5814−5818.
sı
Experimental procedure and characterization data for all
of the products (PDF)
Accession Codes
CCDC 1975384 and 1975388−1975389 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
(4) (a) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M.
Enantioselective C-C Bond Cleavage Creating Chiral Quaternary
Carbon Centers. Org. Lett. 2006, 8, 3379−3381. (b) Barth, R.; Roush,
W. R. Enantioselective Synthesis of α-Methylene-β-Hydroxy Carbox-
ylic Acid Derivatives via a Diastereoselective Aldol/β-Elimination
Sequence: Application to the C(15)-C(21) Fragment of Tedanolide
C. Org. Lett. 2010, 12, 2342−2345.
(5) (a) Bissember, A. C.; Levina, A.; Fu, G. C. A Mild, Palladium-
Catalyzed Method for the Dehydrohalogenation of Alkyl Bromides:
Synthetic and Mechanistic Studies. J. Am. Chem. Soc. 2012, 134,
14232−14237. (b) Wan, B.; Ma, S. Enantioselective Decarboxylative
Amination: Synthesis of Axially Chiral Allenyl Amines. Angew. Chem.,
Int. Ed. 2013, 52, 441−445. (c) Crouch, I. T.; Neff, R. K.; Frantz, D.
E. Pd-Catalyzed Asymmetric β-Hydride Elimination en Route to
Chiral Allenes. J. Am. Chem. Soc. 2013, 135, 4970−4973.
(6) (a) Li, L.; Liu, Y.; Peng, Y.; Yu, L.; Wu, X.; Yan, H. Kinetic
Resolution of β-Sulfonyl Ketones through Enantioselective β-
Elimination using a Cation-Binding Polyether Catalyst. Angew.
Chem., Int. Ed. 2016, 55, 331−335. (b) Liu, Y.; Qin, W.; Yan, H.
Efficient Enrichment of Chiral β-Sulfonyl Ketones through Asym-
metric β-Elimination. Synlett 2016, 27, 2756−2760. (c) Tan, Y.; Luo,
S.; Li, D.; Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H.
Enantioselective Synthesis of anti-syn-Trihalides and anti-syn-anti-
Tetrahalides via Asymmetric β-Elimination. J. Am. Chem. Soc. 2017,
139, 6431−6436.
Wenling Qin − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China;
orcid.org/0000-0002-5654-5785; Email: wenling.qin@
cqu.edu.cn
Hailong Yan − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China;
orcid.org/0000-0003-3378-0237; Email: yhl198151@
cqu.edu.cn
Authors
Fangli Hu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China
Zhili Chen − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China
Yu Tan − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China
Da Xu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China
Shengli Huang − Chongqing Key Laboratory of Natural
Product Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P. R. China
Shiqi Jia − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P. R. China
(7) Glasspoole, B. W.; Crudden, C. M. Cross-coupling between a
racemic secondary alkyl halide and an alkyl borane to produce an
enantioenriched alkyl-alkyl product is one of the final substrate
combinations to succumb to the synthetically powerful Suzuki-
Miyaura methodology. Nat. Chem. 2011, 3, 912−913.
(8) For a thematically similar strategy for the formation of
cyclopropanes, see: (a) Payne, G. B. Cyclopropanes from Reactions
of Ethyl (Dimethylsulfuranylidene)acetate with α,β-Unsaturated
E
https://dx.doi.org/10.1021/acs.orglett.0c00295
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Compounds. J. Org. Chem. 1967, 32, 3351−3355. (b) Kunz, R. K.;
MacMillan, D. W. C. Enantioselective Organocatalytic Cyclo-
propanations. The Identification of a New Class of Iminium Catalyst
Based upon Directed Electrostatic Activation. J. Am. Chem. Soc. 2005,
127, 3240−3241. (c) Zhao, Y.-H.; Zhao, G.; Cao, W.-G. Organo-
catalytic asymmetric cyclopropanation of α,β-unsaturated aldehydes
with arsonium ylides. Tetrahedron. Tetrahedron: Asymmetry 2007, 18,
2462−2467. (d) Cheng, Y.; An, J.; Lu, L.-Q.; Luo, L.; Wang, Z.-Y.;
Chen, J.-R.; Xiao, W.-J. Asymmetric Cyclopropanation of β,γ-
Unsaturated α-Ketoesters with Stabilized Sulfur Ylides Catalyzed by
C2-Symmetric Ureas. J. Org. Chem. 2011, 76, 281−284.
(9) (a) Liu, W.; Li, Y.; Liu, K.; Li, Z. Iron-Catalyzed Carbonylation-
Peroxidation of Alkenes with Aldehydes and Hydroperoxides. J. Am.
Chem. Soc. 2011, 133, 10756−10759. (b) Liu, K.; Li, Y.; Zheng, X.;
Liu, W.; Li, Z. Synthesis of α-ester-β-keto peroxides via iron-catalyzed
carbonylation-peroxidation of α,β-unsaturated esters. Tetrahedron
2012, 68, 10333−10337. (c) Liu, K.; Li, Y.; Liu, W.; Zheng, X.;
Zong, Z.; Li, Z. Efficient and Selective Synthesis of α,β-Epoxy-γ-
Butyrolactones from 2-Peroxy-1,4-Dicarbonyl Compounds. Chem. -
Asian J. 2013, 8, 359−363. (d) Lv, L.; Shen, B.; Li, Z. Total Synthesis
of ( )-Clavilactones A, B, and Proposed D through Iron-Catalyzed
Carbonylation-Peroxidation of Olefin. Angew. Chem., Int. Ed. 2014,
53, 4164−4167. (e) Zong, Z.; Lu, S.; Wang, W.; Li, Z. Iron-catalyzed
alkoxycarbonylation-peroxidation of alkenes with carbazates and T-
Hydro. Tetrahedron Lett. 2015, 56, 6719−6721. (f) Zong, Z.; Bai, X.;
Lu, S.; Li, Z. A general method for synthesis of cis-dicarbonyl epoxides
through DBU/LiBr-cocatalyzed cyclization of α,β-dicarbonyl per-
oxides. Tetrahedron Lett. 2016, 57, 3827−3831. (g) Chen, Y.; Chen,
Y.; Lu, S.; Li, Z. Copper-catalyzed three-component phosphorylation-
peroxidation of alkenes. Org. Chem. Front. 2018, 5, 972−976. (h) Xu,
R.; Li, Z. Ag-catalyzed sulfonylation-peroxidation of alkenes with
sulfonyl hydrazides and T-Hydro. Tetrahedron Lett. 2018, 59, 3942−
3945.
(10) (a) Chung, L. W.; Hayashi, S.; Lundberg, M.; Nakatsu, T.;
Kato, H.; Morokuma, K. Mechanism of Efficient Firefly Bio-
luminescence via Adiabatic Transition State and Seam of Sloped
Conical Intersection. J. Am. Chem. Soc. 2008, 130, 12880−12881.
(b) Kildgaard, S.; de Medeiros, L. S.; Phillips, E.; Gotfredsen, C. H.;
Frisvad, J. C.; Nielsen, K. F.; Abreu, L. M.; Larsen, T. O.
Cyclopiamines C and D: Epoxide Spiroindolinone Alkaloids from
Penicillium sp. CML 3020. J. Nat. Prod. 2018, 81, 785−790. (c) Liu,
F.; Wang, Y.-N.; Li, Y.; Ma, S.-G.; Qu, J.; Liu, Y.-B.; Niu, C.-S.; Tang,
Z.-H.; Li, Y.-H.; Li, L.; Yu, S.-S. Minor Nortriterpenoids from the
Twigs and Leaves of Rhododendron latoucheae. J. Nat. Prod. 2018, 81,
1721−1733. (d) Ernouf, G.; Wilt, I. K.; Zahim, S.; Wuest, W. M.
Epoxy Isonitriles, A Unique Class of Antibiotics: Synthesis of Their
Metabolites and Biological Investigations. ChemBioChem 2018, 19,
2448−2452.
(11) (a) Dembitsky, V. M. Bioactive peroxides as potential
therapeutic agents. Eur. J. Med. Chem. 2008, 43, 223−251.
(b) Pompeo, M. M.; Cheah, J. H.; Movassaghi, M. Total Synthesis
and Anti-Cancer Activity of All Known Communesin Alkaloids and
Related Derivatives. J. Am. Chem. Soc. 2019, 141, 14411−14420.
(12) (a) Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.;
Kim, H.-S.; Ono, K.; Ogura, N.; Wataya, Y. Synthesis and Notable
Antimalarial Activity of Acyclic Peroxides, 1-(Alkyldioxy)-1-
(methyldioxy)cyclododecanes. J. Med. Chem. 2002, 45, 1374−1378.
(b) Gemma, S.; Kunjir, S.; Sanna Coccone, S.; Brindisi, M.; Moretti,
V.; Brogi, S.; Novellino, E.; Basilico, N.; Parapini, S.; Taramelli, D.;
Campiani, G.; Butini, S. Synthesis and Antiplasmodial Activity of
Bicyclic Dioxanes as Simplified Dihydroplakortin Analogues. J. Med.
Chem. 2011, 54, 5949−5953.
(14) (a) Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X.
Advances in Homogeneous and Heterogeneous Catalytic Asymmetric
Epoxidation. Chem. Rev. 2005, 105, 1603−1662. (b) Wang, X.;
Reisinger, C. M.; List, B. Catalytic Asymmetric Epoxidation of Cyclic
Enones. J. Am. Chem. Soc. 2008, 130, 6070−6071. (c) Zhao, Z.; Bagdi,
P. R.; Yang, S.; Liu, J.; Xu, W.; Fang, X. Stereodivergent Access to
Enantioenriched Epoxy Alcohols with Three Stereogenic Centers via
Ruthenium-Catalyzed Transfer Hydrogenation. Org. Lett. 2019, 21,
5491−5494.
(15) (a) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. Catalytic
Enantioselective Peroxidation of α,β-Unsaturated Ketones. J. Am.
Chem. Soc. 2008, 130, 8134−8135. (b) Sun, B.-F.; Hong, R.; Kang, Y.-
B.; Deng, L. Asymmetric Total Synthesis of (−)-Plicatic Acid via a
Highly Enantioselective and Diastereoselective Nucleophilic Epox-
idation of Acyclic Trisubstitued Olefins. J. Am. Chem. Soc. 2009, 131,
10384−10385. (c) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng,
L. Highly enantioselective asymmetric Darzens reactions with a phase
transfer catalyst. Chem. Sci. 2011, 2, 1301−1304. (d) Lu, X.; Deng, L.
Catalytic Asymmetric Peroxidation of α,β-Unsaturated Nitroalkenes
by a Bifunctional Organic Catalyst. Org. Lett. 2014, 16, 2358−2361.
(e) Hu, L.; Lu, X.; Deng, L. Catalytic Enantioselective Peroxidation of
α,β-Unsaturated Aldehydes for the Asymmetric Synthesis of Bio-
logically Important Chiral Endoperoxides. J. Am. Chem. Soc. 2015,
137, 8400−8403.
(16) Nakamura, S.; Takahashi, S. Organocatalytic Enantioselective
Peroxidation of Ketimines Derived from Isatins. Org. Lett. 2015, 17,
2590−2593.
(17) Guo, W.; Liu, Y.; Li, C. Asymmetric Catalytic 1,2-Hydro-
peroxidation of Isatin-Derived Ketimine with Hydrogen Peroxide in
the Crowding Environment of PEGs. Org. Lett. 2017, 19, 1044−1047.
(18) (a) Dussault, P. H.; Trullinger, T. K.; Cho-shultz, S. Chiral Silyl
Ketene Acetals from Thioesters: Reaction with Acetals and
Peroxyacetals to Form 3-Alkoxy- and 3-Peroxyalkanoates. Tetrahedron
2000, 56, 9213−9220. (b) Dussault, P. H.; Trullinger, T. K.; Noor-e-
Ain, F. Opening of Substituted Oxetanes with H2O2 and Alkyl
Hydroperoxides: Stereoselective Approach to 3-Peroxyalcohols and
1,2,4-Trioxepanes. Org. Lett. 2002, 4, 4591−4593. (c) Xu, C.; Raible,
J. M.; Dussault, P. H. Total Synthesis of Peroxyacarnoates A and D:
Metal-Mediated Couplings as a Convergent Approach to Polyunsa-
turated Peroxides. Org. Lett. 2005, 7, 2509−2511. (d) Dai, P.;
Trullinger, T. K.; Liu, X.; Dussault, P. H. Asymmetric Synthesis of 1,2-
Dioxolane-3-acetic Acids: Synthesis and Configurational Assignment
of Plakinic Acid A. J. Org. Chem. 2006, 71, 2283−2292.
(19) (a) Bae, H. Y.; Sim, J. H.; Lee, J.-W.; List, B.; Song, C. E.
Organocatalytic Enantioselective Decarboxylative Aldol Reaction of
Malonic Acid Half Thioesters with Aldehydes. Angew. Chem., Int. Ed.
2013, 52, 12143−12147. (b) Bae, H. Y.; Kim, M. J.; Sim, J. H.; Song,
C. E. Direct Catalytic Asymmetric Mannich Reaction with
Dithiomalonates as Excellent Mannich Donors: Organocatalytic
Synthesis of (R)-Sitagliptin. Angew. Chem., Int. Ed. 2016, 55,
10825−10829. (c) Jiang, X.-L.; Liu, S.-J.; Gu, Y. Q.; Mei, G.-J.; Shi,
F. Catalytic Asymmetric [4 + 1] Cyclization of ortho-Quinone
Methides with 3-Chlorooxindoles. Adv. Synth. Catal. 2017, 359,
3341−3346. (d) Chen, Z.-C.; Chen, Z.; Du, W.; Chen, Y.-C.
Transformations of Modified Morita-Baylis-Hillman Adducts from
Isatins Catalyzed by Lewis Bases. Chem. Rec. 2019, 19, 1−16. (e) Ma,
C.; Jiang, F.; Sheng, F.-T.; Jiao, Y.; Mei, G.-J.; Shi, F. Design and
Catalytic Asymmetric Construction of Axially Chiral 3,3′-Bisindole
Skeletons. Angew. Chem., Int. Ed. 2019, 58, 3014−3020.
(20) (a) Ahmed, N.; Pathe, G. K.; Jheeta, S. SnCl4 or TiCl4: highly
efficient catalysts for the detetrahydropyranylation and demethox-
ymethylation of phenolic ethers and sequential one-pot asymmetric
synthesis of 3-aryl-2-hydroxy-2,3-dihydroindan-1-ones from chalcone
epoxides. RSC Adv. 2015, 5, 63095−63103. (b) Waheed, M.; Ahmed,
N. Pd/Indanone-Based Ligands: An Efficient Catalyst System for
Ullmann-Type, Suzuki-Miyaura, and Mizoroki-Heck Cross-Coupling
Reactions with Aryl Tosylates and Aryl Halides. Synthesis 2017, 49,
4372−4382.
(13) (a) Liang, S.; Wei, Q.; Xue, J.; Sun, Y.; Chen, Z.; Kuang, H.;
Wang, Q. Chemical composition and biological activities of essential
oil from Filifolium sibiricum (L.) Kitam. Nat. Prod. Res. 2016, 30,
2861−2863. (b) Farkasovska, J.; Bugarova, V.; Godocikova, J.;
Majtan, V.; Majtan, J. The role of hydrogen peroxide in the
antibacterial activity of different floral honeys. Eur. Food Res. Technol.
2019, 245, 2739−2744.
F
https://dx.doi.org/10.1021/acs.orglett.0c00295
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(21) (a) Giagou, T.; Meyer, M. P. Kinetic Isotope Effects in
Asymmetric Reactions. Chem. - Eur. J. 2010, 16, 10616−10628.
(b) Simmons, E. M.; Hartwig, J. F. On the Interpretation of
Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by
Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066−
3072.
G
https://dx.doi.org/10.1021/acs.orglett.0c00295
Org. Lett. XXXX, XXX, XXX−XXX