Enantioselective synthesis of fused dihydropyranones via squaramide-catalyzed Michael addition/lactonization cascade reaction

Article abstract of DOI:10.1016/j.tet.2019.03.007

A highly enantioselective (49–99% ee) Michael addition/lactonization cascade process has been developed to construct 3,4-dihydropyran-2-one in the presence of a bifunctional squaramide. Various α,β-unsaturated N-acyl heterocycles were well tolerated and afforded 3,4-dihydropyran-2-ones in moderate to excellent isolated yields (50–99%). Both cyclic and acyclic β-diketones functioned as appropriate donors. The resulting 3,4-dihydropyran-2-ones could be readily converted into oxadecalinones.

Full text of DOI:10.1016/j.tet.2019.03.007

Accepted Manuscript
Enantioselective synthesis of fused dihydropyranones via squaramide-catalyzed
Michael addition/lactonization cascade reaction
Jialing Xian, Lin Chen, Ling Ye, Yin Sun, Zhichuan Shi, Zhigang Zhao, Xuefeng Li
PII:
S0040-4020(19)30266-2
https://doi.org/10.1016/j.tet.2019.03.007
TET 30193
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 December 2018
Revised Date: 19 February 2019
Accepted Date: 6 March 2019
Please cite this article as: Xian J, Chen L, Ye L, Sun Y, Shi Z, Zhao Z, Li X, Enantioselective synthesis
of fused dihydropyranones via squaramide-catalyzed Michael addition/lactonization cascade reaction,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.03.007.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Enantioselective synthesis of fused dihydropyranones via
squaramide-catalyzed Michael addition/lactonization cascade
reaction
Jialing Xian a, Lin Chen b, Ling Ye c, Yin Sun a, Zhichuan Shi a, Zhigang Zhao a, Xuefeng Li a, *
a
College of Chemistry and Environment Protection Engineering, Southwest Minzu University,
Chengdu 610041, China.
b Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial
Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
c
Faculty of Geosciences and Environmental Engineering, Southwest Jiaotong University,
Chengdu 610031, China.
lixuefeng@swun.edu.cn
1

ACCEPTED MANUSCRIPT
Enantioselective synthesis of fused dihydropyranones via
squaramide-catalyzed Michael addition/lactonization cascade
reaction
Jialing Xian a, Lin Chen b, Ling Ye c, Yin Sun a, Zhichuan Shi a, Zhigang Zhao a, Xuefeng Li a, *
a
College of Chemistry and Environment Protection Engineering, Southwest Minzu University,
Chengdu 610041, China.
b Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial
Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
c
Faculty of Geosciences and Environmental Engineering, Southwest Jiaotong University,
Chengdu 610031, China.
lixuefeng@swun.edu.cn
Abstract: A highly enantioselective (49-99% ee) Michael addition/lactonization cascade process
has been developed to construct 3,4-dihydropyran-2-one in the presence of a bifunctional
squaramide. Various α,β-unsaturated N-acyl heterocycles were well tolerated and afforded
3,4-dihydropyran-2-ones in moderate to excellent isolated yields (50-99%). Both cyclic and
acyclic β-diketones functioned as appropriate donors. The resulting 3,4-dihydropyran-2-ones
could be readily converted into oxadecalinones.
Key words: dihydropyranone, α,β-unsaturated N-acylpyrazole, β-diketone, Michael addition,
cascade reaction.
1. Introduction
3,4-Dihydropyran-2-one, also known as enol δ-lactone, is a class of privileged structural
scaffold widely distributed in biologically active natural products and enormous pharmaceuticals.1
The cis-3-aminohexahydrocoumarin derivatives A (Fig. 1), possessing an electron-deficient
aromatic group or a heteroaromatic ring at the 4-position, displayed more powerful cytotoxicity to
SW1116 cells with lower viability rates, when compared with doxorubicin hydrochloride, a potent
1

ACCEPTED MANUSCRIPT
anti-cancer drug.2 Meanwhile, these compounds also exhibited moderate to strong toxicity to
SGC7901 cells.2 In spite of interesting biological activities, 3,4-dihydropyran-2-ones have
attracted intensive attention due to appealing synthetic perspective. The compounds of this type
emerged as the crucial building blocks for the synthesis of a number of natural products. In this
context, elaboration of dihydropyranone B (Fig. 1) allowed the total synthesis of
(–)-7-deoxyloganin to be achieved in four subsequent steps.3 In addition, 3,4-dihydro-2-pyranones
have been recognized as the versatile precursors for the construction of pyridones, γ-lactones,
benzenoid derivatives, etc.1
CO2Me
CO2Me
O
Ar
H
H
H
H
H
N
Ph
O
O
O
O
OH
Me
O
O
Me
HO
O
Me
Me
OH
OH
O
A
B
Cytotoxicity to SW1116
and SGC7901 cells
Key intermediate
for (-)-7-deoxyloganin
(-)-7-Deoxyloganin
Fig. 1. Structurally important 3,4-dihydropyran-2-ones and natural product.
Given the inherent structural importance and attractive biological activity, great effort has been
made to effectively access 3,4-dihydro-2-pyranones,4 especially in an enantioselective fashion2b,5
.
Among all established synthetic approaches, the tandem Michael addition/lactonization process
between 1,3-dicarbonyl compounds or enolate equivalent and α,β-unsaturated carbonyl
compounds is one of the most concise and efficient methods to construct the
3,4-dihydropyran-2-one framework and represents the main preparative pathway. In this context,
N-heterocyclic carbene (NHC) has played a particular active role in this field among all utilized
catalysts.1 A variety of 3,4-dihydro-2-pyranones were smoothly generated in a highly
enantioenriched manner, using α,β-unsaturated acylazolium ions6 or azolium enol/enolates7 as the
crucial reactive intermediates. As for all the often-used acceptors, α,β-unsaturated carboxylic acid
derivatives remain a type of challenging substrate for the titled domino process.8 In this regard,
α,β-unsaturated pyrazolamides have been successfully employed by Kanemasa group to access
enol δ-lactones with high levels of enantiopurities under double catalytic condition.5a However, in
addition to Nickel complex, an external base was required to initiate this domino sequence.
2

ACCEPTED MANUSCRIPT
Moreover, stoichiometric acetic anhydride was essential to prevent the formation of by-product.
Unsaturated N-acylthiazolidinethiones were employed by Evans group to construct
dihydropyranones in a stepwise manner.5b After the initial Michael addition, additional base was
required to promote the further annulation process as well. Moreover, Du5e and Albrecht5i have
confirmed α,β-unsaturated N-acylated succinimides and β,γ-unsaturated-α-ketophosphonates to be
competent partners for the tandem process of this type, respectively. However, the optical purities
of the most products awaited further improvement. Therefore, further exploration of efficient
catalytic method for the synthesis of enantioenriched enol δ-lactone via α,β-unsaturated carboxylic
acid derivatives has become an urgent task.
Based on our continuous effort on the asymmetric Michael addition involving α,β-unsaturated
carboxylic acid derivatives,9 herein we would like to present a highly enantioselective domino
Michael addition/lactonization sequence mediated by a chiral squaramide. A wide range of cyclic
or acyclic β-diketones smoothly reacted with α,β-unsaturated N-acylpyrazoles10, delivering enol
δ-lactones in high yields and excellent enantiomeric purities. Moreover, the reactivity of this
cascade process depended closely on the electron-withdrawing character and leaving ability of the
heterocycles besides carbonyl group within the context of the acceptor.
2. Result and discussion
We commenced with our investigation using dimedone 1a and α,β-unsaturated pyrazolamide 2a
as the model substrates. Gratifyingly, the desired [3+3] annulation product 3aa was smoothly
obtained with promising enantioselectivity in the presence of quinine-based bifunctional thiourea
C1,11 albeit the reactivity awaited further improvement (Table 1, entry 1). Other cinchona
alkaloid-derived thioureas C2-C4 delivered enol δ-lactone with slightly poorer optical purity
(entries 2-4 vs entry 1). We successively turned our attention to evaluate the effect of solvent. It
was indicated that the reactivity of this domino process was correlated closely with the polarity of
the solvent. In general, the reactivity increased as the polarity of the solvent increased with
exception of acetonitrile (ACN) (entries 5-9). Among all solvent studied, ethyl acetate (EtOAc)
emerged as the preferable one due to the superior reactivity and comparable enantioselectivity.
Further optimization study disclosed that the bifunctional squaramide C5 proved to be the
favorable catalyst in terms of reactivity and enantiocontrol.12 Notably, extending space between
3

ACCEPTED MANUSCRIPT
the squaramide moiety and the aryl group embedded in the catalyst resulted in dramatically
erosion of enantiomeric excess and reactivity (entry 11 vs entry 10).12 Moreover, highest isolated
yield was achieved when this formal [3+3] cycloaddition reaction was performed with a 2:1 ratio
of donor 1a to acceptor 2a; either increasing or reducing the substrate ratio of 1a to 2a led to
diminished reactivity (entries 12-14 vs entry 10).
Table 1 Optimization of reaction conditions.a
Entry
1
Cat.
C1
C2
C3
C4
C1
C1
C1
C1
C1
C5
C6
C5
C5
C5
Solvent
toluene
toluene
toluene
toluene
PhCF3
DCM
Yield (%) b
ee (%) c
92
37
44
44
54
76
56
78
91
65
90
90
82
68
85
2
82
3
-87
-87
86
4
5
6
91
7
THF
92
8
EtOAc
ACN
87
9
95
10
11
12d
13e
14f
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
97
85
97
96
97
a
Unless otherwise noted, the reactions were performed with 0.2 mmol of 1a, 0.1 mmol of α,β-unsaturated
pyrazolamide 2a, 20 mol % of catalyst in 1 mL of solvent at 40 oC for 168 hours.
b Isolated yield after flash chromatography on silica gel.
c Determined by HPLC on chiral OJ-H column.
4

ACCEPTED MANUSCRIPT
d Performed with 0.15 mmol of 1a, 0.1 mmol of 2a.
e Performed with 0.1 mmol of 1a, 0.1 mmol of 2a.
f Performed with 0.1 mmol of 1a, 0.2 mmol of 2a.
CF3
R
N
OMe
N
H
N
H
O
N
F3C
NH
NH
NH
NH
S
CF3
CF3
S
NH
NH
N
n
N
H
O
F3C
CF3
R
C1: R = OMe
C2: R = H
C3: R = OMe
C4: R = H
C5: n = 0
C6: n = 1
Fig. 2. The structure of bifunctional organocatalysts.
Once the optimal reaction condition was established, a range of various α,β-unsaturated
pyrazolamides 2 were examined to explore the substrate generality of this protocol. As list in table
2, the Michael addition/lactonization sequence proceeded smoothly with a variety of
chloride-substituted N-acylpyrazoles 2b-2j of different electronic property in ethyl acetate at 40 oC
promoted by 20 mol% of bifunctional squaramide C5, allowing access to the annulation products
3ab-3aj with excellent enantiopurities (Table 2, 2-10). Generally, the electron-deficient acceptors
2c, 2d, 2f-2h displayed slightly higher reactivity in comparison with electron-rich acceptors 2i and
2j (entries 3, 4, 6-8 vs entries 9 and 10). This tandem reaction was very sensitive to steric
hindrance imposed by substituents on the phenyl group. Significant decrease of isolated yield was
observed in the case of ortho-substituted substrates 2b and 2e, when compared with the
corresponding para- and meta-substituted substrates (entry 2 vs entries 3 and 4, entry 5 vs entry 6).
2k, possessing a bulky naphthyl group on the terminal of the double bond, was well tolerated by
this catalytic system, giving dihydropyranone 3ak in quantitative yield and 95% ee (entry 11). The
heteroaromatic acceptor 2l readily participated in this domino reaction, allowing access to 3al with
high degrees of optical purity (entry 12). In addition to chloride-substituted N-acylpyrazoles,
bromide- and iodine-containing analogues 2m-2o were suitable partners as well (entries 13-15). In
particular, almost enantiomerically pure product 3am was formed in the case of furyl-substituted
5

ACCEPTED MANUSCRIPT
acceptor 2n. Remarkably, halogen-free N-acylpyrazoles 2p and 2q were compatible with this
cascade sequence, even exhibiting higher reactivities in contrast with the corresponding
chloride-containing compounds 2a and 2g (entry 16 vs entry 1, entry 17 vs entry 7). The absolute
configuration of the enol δ-lactone 3aa was established as S via comparison of HPLC traces and
optical rotation value with that of literatures reported,5a,5e other adducts were assigned by analogy.
Table 2 Substrate scope of α,β-unsaturated pyrazolamides.a
Entry
1
R1 /X (2)
Time (h)
168
168
168
168
168
168
168
168
168
168
120
168
144
168
168
120
168
Yield (%) b
ee (%) c
97
3
Ph/Cl (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
90
53
90
90
50
75
77
85
73
80
99
94
99
94
90
99
79
2
o-ClC6H4/Cl (2b)
m-ClC6H4/Cl (2c)
p-ClC6H4/Cl (2d)
o-BrC6H4/Cl (2e)
p-BrC6H4/Cl (2f)
p-FC6H4/Cl (2g)
p-CF3C6H4/Cl (2h)
p-MeC6H4/Cl (2i)
p-MeOC6H4/Cl (2j)
2-naphthyl/Cl (2k)
2-thienyl/Cl (2l)
Ph/Br (2m)
96
3
99
4
96
5
90
6
96
7
96
8
97
9
98
10
11
12
13
14
15
16
17
93
3aj
3ak
3al
95
97
96
3aa
3am
3aa
3aa
3ag
2-furyl/Br (2n)
Ph/I (2o)
99
96
Ph/H (2p)
96
p-FC6H4/H (2q)
96
a
Unless otherwise noted, the reactions were performed with 0.2 mmol of 1a, 0.1 mmol of α,β-unsaturated
6

ACCEPTED MANUSCRIPT
pyrazolamide 2, 20 mol % of C5 in 1 mL of EtOAc at 40 oC for due reaction time.
b Isolated yield after flash chromatography on silica gel.
c Determined by HPLC analysis on chiral stationary phases.
Having identified α,β-unsaturated N-acylpyrazole 2 as the appropriate counterpart, we
subsequently explored the substrate scope of other cinnamic N-acyl heterocycles. To our delight,
the titled cascade reaction worked well with a range of acceptors containing different heterocycles,
including pyrrole (Ar1),13 imidazole (Ar2),14 benzotriazole (Ar3)15 and 1,2,4-triazole (Ar4)6k (Table
3, entries 1-4). Generally speaking, the reactivity of these acceptors depended closely on
electron-withdrawing character and leaving ability of the heteroaromatic residues beside the
carbonyl groups (Fig. 3).8 This domino reaction proceeded via the initial Michael addition and the
following lactonization to afford the resulting enol δ-lactone. The rate of Michael addition
depended strictly on the electron-withdrawing ability of the heterocyclic residue (Ar), whose
enhancement lowered the lowest unoccupied molecular orbital (LUMO) energy and favored the
conjugate addition. Meanwhile, the lactonization process correlated directly with the cleavage of
amide-type C(O)-N bond. The cleavage easiness of heterocycle was a function of the anion
stability, and therefore a rough measure was taken into account by the pKa value of the
corresponding conjugated acid (ArH). As depicted in Figure 2, 4a and 4b were relatively poorer
Michael acceptors. Moreover, the leaving ability of pyrrole and imidazole residues was inferior to
benzotriazole and 1,2,4-triazole residues. As a result, cinnamic N-acyl pyrrole 4a and cinnamic
N-acyl imidazole 4b furnished enol δ-lactone 3aa just in moderate isolated yield even after 168
hours. In contrast, the domino reaction went to completion after 48 hours and provided the target
product 3aa in almost quantitative isolated yield in the case of 4c and 4d. Moreover, variation of
heterocyclic substituents from pyrazoles to 1,2,4-triazles also gave rise to considerable
enhancement of reactivity. Although those N-acyl pyrazoles, 2b, 2e-2g, 2i and 2j afforded
unsatisfactory isolate yields even after 168 hours (Table 2, entries 2, 5-7, 9 and 10), complete
conversions (90-99% yield) were detected for the corresponding N-acyl 1,2,4-triazoles 4e-4j only
after 48-72 hours (entries 5-10). Inspired by these encouraging results, the aliphatic substrate 4k
was also utilized and treated with dimedone 1a, resulting in formation of 3an in synthetically
useful yield and prominent enantiomeric excess (entry 11).
7

ACCEPTED MANUSCRIPT
Table 3 Substrate scope of N-acyl heterocycles. a
O
R1
O
O
O
C5 (20 mol%)
+
R1
Ar
N
EtOAc, 40 oC
Me
Me
Me
Me
O
O
1a
3
4
N
Ar1 =
Ar2 =
Ar3=
N
Ar4 =
N
N
N
N
N
N
Entry
R1/Ar (4)
Time (h)
168
168
48
Yield (%) b
ee (%)c
94
3
1
Ph/Ar1 (4a)
Ph/Ar2 (4b)
Ph/Ar3 (4c)
Ph/Ar4 (4d)
54
53
99
99
90
94
94
94
99
90
90
3aa
3aa
3aa
3aa
3ab
3ae
3af
3ag
3ai
2
96
3
94
4
48
94
5
o-ClC6H4/Ar4 (4e)
o-BrC6H4/Ar4 (4f)
p-BrC6H4/Ar4 (4g)
p-FC6H4/Ar4 (4h)
p-MeC6H4/Ar4 (4i)
48
91
6
48
91
7
48
92
8
48
90
9
48
93
10
11
p-MeOC6H4/Ar4 (4j)
Me/Ar4 (4k)
72
92
3aj
3an
72
93
a Unless otherwise noted, the reactions were performed with 0.2 mmol of 1a, 0.1 mmol of 4, 20 mol% of C5 in 1
mL of EtOAc at 40 oC for due reaction time.
b Isolated yield after flash chromatography on silica gel.
c Determined by HPLC on chiral OJ-H column.
8

ACCEPTED MANUSCRIPT
Fig. 3. The electron-withdrawing character and leaving ability of heterocycles.
Next, the substrate scope was also investigated with respect to β-diketones.
1,3-Cyclohexanedione even displayed higher reactivity than dimedone 1a (Table 4, entry 1).
Although 1,3-cyclopentadione was totally inert under the standard conditions, the seven-member
analogue, 1,3-cycloheptanedione, allowed efficient formation of fused product 3cl with 98% ee at
elevated temperature (entry 2). Acyclic β-diketones were appropriate donors as well, but
prolonged reaction time was required in contrast with cyclic ones (entries 3 and 4). Delightfully,
excellent enantiopurities were obtained for these β-diketones except acetylacetone via our
approach, albeit the pioneering study indicated that all these compounds were challenging donors
owing to poor enantiocontrol.5e
Table 4 Substrate scope of 1,3-dicarbonyl compounds. a
a Unless otherwise noted, the reactions were performed with 0.2 mmol of 1a, 0.1 mmol of 4, 20 mol% of C5 in 1
mL of EtOAc at 40 oC for due reaction time. Isolated yield after flash chromatography on silica gel. The
9

ACCEPTED MANUSCRIPT
enantioselectivity was determined by HPLC analysis on chiral stationary phases.
b Performed at 60 oC.
The enantioenriched dihydropyranones generated via this domino process are synthetically
versatile materials. Alcoholysis of 3aa and further protection as acetate occurred smoothly to
afford product 5 in good yield without compromise of enantiopurity (Scheme 1, a). In addition,
chemoselective reduction of ester motif worked properly with 2.1 equiv of sodium borohydride
under mild reaction conditions (Scheme 1, b).16 Although a slight loss of optical purity was
observed in the case of 6b, other dihydropyranones gave rise to the desired oxadecalinones17
without detectable racemization. Notably, oxadecalinones are the core skeletons of many
interesting natural products, including arisugacin A,18 phomactin A19 and orevactaene20.
O
Ph
O
Ph
O
1. MeOH, 50 oC
OMe
(a)
2. AcCl, DMAP, THF, 0 oC-rt
Me
Me
Me
Me
O
O
OAc
5
3aa, 94% ee
98% yield, 94% ee
O
Ar
O
Ar
NaBH4 (2.1 eq)
MeOH, 0 oC-rt
(b)
Me
Me
Me
Me
O
O
O
6a: Ar = Ph, 98% yield, 94% ee
3aa: Ar = Ph, 94% ee
6b: Ar = p-ClC6H4, 92% yield, 92% ee
6c: Ar = p-MeC6H4, 92% yield, 93% ee
6d: Ar = Furanyl, 90% yield, 94% ee
3ac: Ar = p-ClC6H4, 96% ee
3ai: Ar = p-MeC6H4, 93% ee
3am: Ar = Furanyl, 94% ee
Scheme 1. Synthetic manipulations of dihydropyranone.
To account for the observed stereochemical outcome of this cascade reaction, a plausible
transition state model was proposed and described in Scheme 2.21 The squaramide moiety of
catalyst C5 was believed to form dual hydrogen-bondings with carbonyl group and nitrogen
embedded in pyrazole motif, thereby increasing the electrophilicity of α,β-unsaturated
pyrazolamide. Meanwhile, dimedone was deprotonated and orientated by the tertiary amine
subunit of catalyst C5. Therefore, the Michael addition occurred via attack Re-face of acceptor.
The following proton transfer proceeded within the conjugated addition intermediate C, giving
10

ACCEPTED MANUSCRIPT
rise to the corresponding enolate anion D. This resulting enolate anion attacked the amide
carbonyl group to afford cyclic intermediate E. The consequent C-N cleavage generated the
desired dihydropyranone 3aa, accompanied by the release of pyrazole.
N
CF3
O
O
OMe
Me
Me
F3C
N
H
N
O
H
O
N
H
N
Michael addition
H
O
N
H
H
O
N
N
Ph
O
C
Ph
Re face attack
O
Me
Me
Proton
transfer
O
Ph
O
Ph
O
Me
Me
O
O
N
H
N
N
N
O
Me
Me
Me
Me
O
O
H
Ph
O
N
N
E
D
3aa
H
Scheme 2. Proposed reaction pathway for the cascade sequence.
3. Conclusion
In conclusion, a highly enantioselective (49-99% ee) Michael addition/lactonization cascade
process has been developed to construct 3,4-dihydropyran-2-one in the presence of a bifunctional
squaramide. Various α,β-unsaturated N-acyl heterocycles were well tolerated and afforded
3,4-dihydropyran-2-ones in moderate to excellent isolated yields (50-99%). Both cyclic and
acyclic β-diketones functioned as appropriate donors. The resulting 3,4-dihydropyran-2-ones
could be readily converted into oxadecalinones. Moreover, a single squaramide was sufficient to
accomplish this enantioselective transformation, and no additional additive was required in
comparison with previous protocol.5a,5b The related domino reaction employing acceptor of this
type is well underway in our lab.
Acknowledgements
This work is financially supported by the National Natural Science Foundation of China (No.
11

ACCEPTED MANUSCRIPT
21402163) and the Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province
(ARRLKF18-12). Jialing Xian gratefully acknowledges the Graduate Innovation Project of
Southwest Minzu University (No. CX2017SZ017). Yin Sun acknowledges the Undergraduate
Innovation Project of Southwest Minzu University (No. S201810656022).
References
1. Albanese, D. C. M.; Gaggero, N. Eur. J. Org. Chem. 2014, 2014, 5631.
2. (a) Shi, F.; Dai, A.-X.; Zhang, S.; Zhang, X.-H.; Tu, S.-J. Eur. J. Med. Chem. 2011, 46, 953; (b)
Yang, X.; Zhang, Y.-C.; Zhu, Q.-N.; Tu, M.-S.; Shi, F. J. Org. Chem. 2016, 81, 5056.
3. Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836.
4. (a) Kobayashi, S.; Moriwaki, M. Synlett 1997, 1997, 551; (b) Katritzky, A. R.; Denisko, O. V. J.
Org. Chem. 2002, 67, 3104; (c) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009,
131, 14176; (d) Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623; (e) De Sarkar, S.;
Studer, A. Angew. Chem. Int. Ed. 2010, 49, 9266; (f) Yao, C.; Wang, D.; Lu, J.; Li, T.; Jiao, W.;
Yu, C. Chem. Eur. J. 2012, 18, 1914; (g) Lu, Y.; Tang, W.; Zhang, Y.; Du, D.; Lu, T. Adv. Synth.
Catal. 2013, 355, 321.
5. (a) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979; (b) Evans, D. A.;
Thomson, R. J.; Franco, F. J. Am. Chem. Soc. 2005, 127, 10816; (c) Tozawa, T.; Nagao, H.;
Yamane, Y.; Mukaiyama, T. Chem. Asian J. 2007, 2, 123; (d) Wang, J.; Yu, F.; Zhang, X.; Ma, D.
Org. Lett. 2008, 10, 2561; (e) Zhao, B.-L.; Du, D.-M. Tetrahedron: Asymmetry 2014, 25, 310; (f)
Zhang, M.-L.; Wu, Z.-J.; Zhao, J.-Q.; Luo, Y.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett.
2016, 18, 5110; (g) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am.
Chem. Soc. 2011, 133, 2714; (h) Young, C. M.; Stark, D. G.; West, T. H.; Taylor, J. E.; Smith, A.
D. Angew. Chem. Int. Ed. 2016, 55, 14394; (i) Kowalczyk, D.; Albrecht, Ł. Tetrahedron Lett. 2018,
59, 2636.
6. (a) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010, 132,
8810; (b) Zhu, Z.-Q.; Zheng, X.-L.; Jiang, N.-F.; Wan, X.; Xiao, J.-C. Chem. Commun. 2011, 47,
8670; (c) Ren, Q.; Li, M.; Yuan, L. Org. Biomol. Chem. 2017, 15, 1329; (d) Rong, Z.-Q.; Jia,
M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080; (e) Lin, Y.; Yang, L.; Deng, Y.; Zhong, G. Chem.
Commun. 2015, 51, 8330; (f) Lu, H.; Liu, J.-Y.; Li, C.-G.; Lin, J.-B.; Liang, Y.-M.; Xu, P.-F.
Chem. Commun. 2015, 51, 4473; (g) Xie, D.; Shen, D.; Chen, Q.; Zhou, J.; Zeng, X.; Zhong, G. J.
Org. Chem. 2016, 81, 6136; (h) Sun, F.-G.; Sun, L.-H.; Ye, S. Adv. Synth. Catal. 2011, 353, 3134;
(i) Wang, G.; Chen, X.; Miao, G.; Yao, W.; Ma, C. J. Org. Chem. 2013, 78, 6223; (j) Mo, J.; Shen,
L.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 8588; (k) Ni, Q.; Xiong, J.; Song, X.; Raabe, G.;
Enders, D. Chem. Commun. 2015, 51, 14628; (l) Zhu, L.; Yu, C.; Li, T.; Wang, Y.; Lu, Y.; Wang,
12

ACCEPTED MANUSCRIPT
W.; Yao, C. Org. Biomol. Chem. 2016, 14, 1485; (m) Que, Y.; Lu, Y.; Wang, W.; Wang, Y.; Wang,
H.; Yu, C.; Li, T.; Wang, X.-S.; Shen, S.; Yao, C. Chem. Asian J. 2016, 11, 678.
7. (a) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem. Eur. J. 2008, 14, 8473; (b) Kaeobamrung, J.;
Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci. USA 2010, 107, 20661; (c) Fang, X.; Chen,
X.; Chi, Y. R. Org. Lett. 2011, 13, 4708; (d) Fu, Z.; Sun, H.; Chen, S.; Tiwari, B.; Li, G.; Robin
Chi, Y. Chem. Commun. 2013, 49, 261; (e) Mo, J.; Yang, R.; Chen, X.; Tiwari, B.; Chi, Y. R. Org.
Lett. 2013, 15, 50; (f) Zhao, X.; Ruhl, K. E.; Rovis, T. Angew. Chem. Int. Ed. 2012, 51, 12330; (g)
He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088; (h) He, M.; Beahm, B. J.;
Bode, J. W. Org. Lett. 2008, 10, 3817; (i) Leckie, S. M.; Brown, T. B.; Pryde, D.; Lebl, T.; Slawin,
A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2013, 11, 3230; (j) Jian, T.-Y.; Chen, X.-Y.; Sun,
L.-H.; Ye, S. Org. Biomol. Chem. 2013, 11, 158; (k) Davies, A. T.; Pickett, P. M.; Slawin, A. M.
Z.; Smith, A. D. ACS Catal. 2014, 4, 2696.
8. Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2015, 115, 9922.
9. (a) Zheng, Y.; Yao, Y.; Ye, L.; Shi, Z.; Li, X.; Zhao, Z.; Li, X. Tetrahedron 2016, 72, 973; (b) Liu,
Y.; Ye, L.; Shi, Z.; Yang, X.; Zhao, Z.; Li, X. Chirality 2018, 30, 1287.
10. (a) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394; (b) Sibi, M. P.; Itoh, K. J. Am.
Chem. Soc. 2007, 129, 8064; (c) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Adv.
Synth. Catal. 2012, 354, 1141; (d) Zhang, J.; Liu, X.; Wang, R. Chem. Eur. J. 2014, 20, 4911; (e)
Wang, G.; Tang, Y.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. Chem. Eur. J. 2017, 23, 554; (f)
Meninno, S.; Volpe, C.; Lattanzi, A. Chem. Eur. J. 2017, 23, 4547; (g) Zhang, Y.; Liao, Y.; Liu,
X.; Yao, Q.; Zhou, Y.; Lin, L.; Feng, X. Chem. Eur. J. 2016, 22, 15119; (h) Dong, X.-Q.; Fang, X.;
Tao, H.-Y.; Zhou, X.; Wang, C.-J. Chem. Commun. 2012, 48, 7238; (i) Ishihara, K.; Fushimi, M.
Org. Lett. 2006, 8, 1921; (j) Yao, Q.; Wang, Z.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. J. Org. Chem.
2015, 80, 5704; (k) Tan, B.; Hernández-Torres, G.; Barbas III, C. F. Angew. Chem. Int. Ed. 2012,
51, 5381; (l) Li, T.-Z.; Wang, X.-B.; Sha, F.; Wu, X.-Y. J. Org. Chem. 2014, 79, 4332; (m) Li,
T.-Z.; Jiang, Y.; Guan, Y.-Q.; Sha, F.; Wu, X.-Y. Chem. Commun. 2014, 50, 10790; (n) Li, T.-Z.;
Xie, J.; Jiang, Y.; Sha, F.; Wu, X.-Y. Adv. Synth. Catal. 2015, 357, 3507; (o) Agrawal, S.; Molleti,
N.; Singh, V. K. Chem. Commun. 2015, 51, 9793; (p) Jiang, Y.; Fu, J.-H.; Li, T.-Z.; Sha, F.; Wu,
X.-Y. Org. Biomol. Chem. 2016, 14, 6435; (q) Luo, Y.; Xie, K.-X.; Yue, D.-F.; Zhang, X.-M.; Xu,
X.-Y.; Yuan, W.-C. Tetrahedron 2017, 73, 6217; (r) Zhang, H.-J.; Shi, C.-Y.; Zhong, F.; Yin, L. J.
Am. Chem. Soc. 2017, 139, 2196; (s) Zhang, Z.-G.; Fu, J.-H.; Sha, F.; Wu, X.-Y. Tetrahedron 2018,
74, 3557; (t) Cui, L.; Lv, D.; Wang, Y.; Fan, Z.; Li, Z.; Zhou, Z. J. Org. Chem. 2018, 83, 4221; (u)
Luo, Y.; Xie, K.-X.; Yue, D.-F.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Org. Biomol. Chem. 2018,
16, 3372.
11. Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 2005, 603.
12. Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416.
13. Vakulya, B.; Varga, S.; Soós, T. J. Org. Chem. 2008, 73, 3475.
14. Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9474.
13

ACCEPTED MANUSCRIPT
15. Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326, 120.
16. Hombrecher, H.; Margaretha, P.; Tissot, P. Helv. Chim. Acta 1986, 69, 1681.
17. Rueping, M.; Sugiono, E.; Merino, E. Chem. Eur. J. 2008, 14, 6329.
18. Sunazuka, T.; Handa, M.; Nagai, K.; Shirahata, T.; Harigaya, Y.; Otoguro, K.; Kuwajima, I.;
Ōmura, S. Org. Lett. 2002, 4, 367.
19. Diaper, C. M.; Goldring, W. P. D.; Pattenden, G. Org. Biomol. Chem. 2003, 1, 3949.
20. Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002, 67, 5176.
21. Xu, D. Q.; Wang, Y. F.; Zhang, W.; Luo, S. P.; Zhong, A. G.; Xia, A. B.; Xu, Z. Y. Chem. Eur. J.
2010, 16, 4177.
14